6-HETEROCYCLIC IMIDAZO[1,2-a]PYRIDINE-2-CARBOXAMIDE DERIVATIVES, PREPARATION AND THERAPEUTIC USE THEREOF

ABSTRACT

Compounds of formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             in which: 
             X, R 1 , R 2 , R 3  and R 4  are as defined in the disclosure, or an acid addition salt thereof; and therapeutic use thereof.

This application is a divisional application of application U.S. patentapplication Ser. No. 12/828,374, filed Jul. 1, 2010, which is acontinuation of International application No. PCT/FR2008/001,836, filedDec. 31, 2008. The contents of each of the aforementioned applicationsare incorporated by reference.

The present invention relates to imidazo[1,2-a]pyridine-2-carboxamidederivatives, to their preparation and to their therapeutic use in thetreatment or prevention of diseases involving the nuclear receptorsNurr-1, also known as NR4A2, NOT, TINUR, RNR-1 and HzF3.

One subject of the present invention is the compounds of formula (I):

in which:

-   X represents a phenyl group optionally substituted with one or more    groups chosen, independently of each other, from the following atoms    or groups: halogen, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, NRaRb, cyano,    (C₁-C₆)alkoxycarbonyl, the groups (C₁-C₆)alkyl and (C₁-C₆)alkoxy    being optionally substituted with one or more halogen atoms;-   R₁ represents a hydrogen atom, a halogen, a group (C₁-C₆)alkoxy, a    group (C₁-C₆)alkyl or a group NRaRb, the alkyl and alkoxy groups    possibly being substituted with one or more halogen, hydroxyl or    amino, or a group (C₁-C₆)alkoxy;-   R₂ represents an unsaturated, partially saturated or totally    saturated aromatic heterocyclic group, optionally substituted with    one or more groups chosen, independently of each other, from the    following atoms or groups: hydroxyl, (C₁-C₆)alkoxy, halogen, cyano,    NRaRb, CO—R₅, CO—NR₆R₇, —CO—O—R₈, —NR₉—CO—R₁₀, a group (C₁-C₆)alkyl,    which is itself optionally substituted with one or more hydroxyl or    NRaRb, an oxido group;-   R₃ represents a hydrogen atom, a group (C₁-C₆)alkyl, a group    (C₁-C₆)alkoxy or a halogen atom;-   R₄ represents a hydrogen atom, a group (C₁-C₄)alkyl, a group    (C₁-C₄)alkoxy or a fluorine atom;-   R₅ represents a hydrogen atom, a phenyl group or a group    (C₁-C₆)alkyl;-   R₆ and R₇, which may be identical or different, represent a hydrogen    atom or a group (C₁-C₆)alkyl or form, with the nitrogen atom, a 4-    to 7-membered ring optionally including another heteroatom chosen    from N, O and S;-   R₈ represents a group (C₁-C₆)alkyl;-   R₉ and R₁₀, which may be identical or different, represent a    hydrogen atom or a group (C₁-C₆)alkyl;-   Ra and Rb are, independently of each other, hydrogen or (C₁-C₆)alkyl    or form, with the nitrogen atom that bears them, a 4- to 7-membered    ring, optionally including another heteroatom chosen from N, O and    S;    with the exception of    N-(4-bromophenyl)-6-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-2-carboxamide;    in the form of the base or of an acid-addition salt.

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They may thus exist in the form of enantiomers ordiastereoisomers. These enantiomers and diastereoisomers, and alsomixtures thereof, including racemic mixtures, form part of theinvention.

The compounds of formula (I) may exist in the form of bases or ofacid-addition salts. Such addition salts form part of the invention.These salts may be prepared with pharmaceutically acceptable acids, butthe salts of other acids that are useful, for example, for purifying orisolating the compounds of formula (I) also form part of the invention.

The compounds of formula (I) may also exist in the form of hydrates orsolvates, i.e. in the form of associations or combinations with one ormore water molecules or with a solvent. Such hydrates and solvates alsoform part of the invention.

N-(4-Bromophenyl)-6-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-2-carboxamide,which is specifically excluded from formula (I) according to theinvention, is cited in chemical libraries under the numberRN=797785-86-5.

In the context of the present invention, the following definitionsapply:

-   -   a halogen atom: a fluorine, a chlorine, a bromine or an iodine;    -   an alkyl group: a linear, branched or cyclic saturated aliphatic        group, optionally substituted with a linear, branched or cyclic        saturated alkyl group. Examples that may be mentioned include        methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        methylcyclopropyl, etc. groups;    -   an alkenyl group: a linear or branched, monounsaturated or        polyunsaturated aliphatic group comprising, for example, one or        two ethylenic unsaturations;    -   an alkoxy group: a radical O-alkyl in which the alkyl group is        as defined previously;    -   a heterocyclic group: an unsaturated, partially saturated or        totally saturated monocyclic or bicyclic aromatic group        comprising from 5 to 10 atoms including 1 to 4 heteroatoms        chosen from N, O and S. Examples of heterocyclic groups that may        be mentioned include: pyrrole, furan, thiophene, pyrazole,        imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole,        thiazole, isothiazole, thiadiazole, pyridine, pyrimidine,        pyrazine, pyridazine, triazine, pyrrolopyrrole,        pyrroloimidazole, pyrrolopyrazole, pyrrolotriazole,        imidazoimidazole, imidazopyrazole, imidazotriazole, indole,        isoindole, benzimidazole, indazole, indolizine, benzofuran,        isobenzofuran, benzothiophene, benzo[c]thiophene,        pyrrolopyridine, imidazopyridine, pyrazolopyridine,        triazolopyridine, tetrazolopyridine, pyrrolopyrimidine,        imidazopyrimidine, pyrazolopyrimidine, triazolopyrimidine,        tetrazolopyrimidine, pyrrolopyrazine, imidazopyrazine,        pyrazolopyrazine, triazolopyrazine, tetrazolopyrazine,        pyrrolopyridazine, imidazopyridazine, pyrazolopyridazine,        triazolopyridazine, tetrazolopyridazine, pyrrolotriazine,        imidazotriazine, pyrazolotriazine, triazolotriazine,        tetrazolotriazine, furopyridine, furopyrimidine, furopyrazine,        furopyridazine, furotriazine, oxazolopyridine,        oxazolopyrimidine, oxazolopyrazine, oxazolopyridazine,        oxazolotriazine, isoxazolopyridine, isoxazolopyrimidine,        isoxazolopyrazine, isoxazolopyridazine, isoxazolotriazine,        oxadiazolopyridine, oxadiazolopyrimidine, oxadiazolopyrazine,        oxadiazolopyridazine, oxadiazolotriazine, benzoxazole,        benzisoxazole, benzoxadiazole, thienopyridine, thienopyrimidine,        thienopyrazine, thienopyridazine, thienotriazine,        thiazolopyridine, thiazolopyrimidine, thiazolopyrazine,        thiazolopyridazine, thiazolotriazine, isothiazolopyridine,        isothiazolopyrimidine, isothiazolopyrazine,        isothiazolopyridazine, isothiazolotriazine, thiadiazolopyridine,        thiadiazolopyrimidine, thiadiazolopyrazine,        thiadiazolopyridazine, thiadiazolotriazine, benzothiazole,        benzoisothiazole, benzothiadiazole, quinoline, isoquinoline,        cinnoline, phthalazine, quinoxaline, quinazoline, naphthyridine,        benzotriazine, pyridopyrimidine, pyridopyrazine,        pyridopyridazine, pyridotriazine, pyrimidopyrimidine,        pyrimidopyrazine, pyrimidopyridazine, pyrimidotriazine,        pyrazinopyrazine, pyrazinopyridazine, pyrazinotriazine,        pyridazinopyridazine, pyridazinotriazine; these groups possibly        being partially unsaturated or saturated.

Examples of heterocyclic groups that may also be mentioned includedioxolane and indazoline groups.

This heterocyclic group at R₂ is not bonded to theimidazo[1,2-a]pyridine via a nitrogen if it is a nitrogenous saturatedmonocyclic heterocyclic group.

Various subgroups of compounds, which also form part of the invention,are defined hereinbelow.

Among the compounds that are subjects of the invention, a first group ofcompounds is constituted by the compounds of formula (I) as definedpreviously, in which:

X represents a phenyl group optionally substituted with one or morehalogen atoms or cyano groups;

the other groups being as defined previously.

Among the compounds that are subjects of the invention, a second groupof compounds is constituted by the compounds of formula (I) as definedpreviously, in which:

X represents a phenyl group optionally substituted with one or morefluorine or chlorine atoms or cyano groups;

the other groups being as defined previously.

Among the compounds that are subjects of the invention, a third group ofcompounds is constituted by the compounds of formula (I) as definedpreviously, in which R₂ represents an unsaturated, partially saturatedor totally saturated monocyclic or bicyclic aromatic heterocyclic group,comprising from 5 to 10 atoms including 1 to 4 heteroatoms chosen fromN, O and S, with the exclusion of a piperidine group, the saidheterocycle being optionally substituted with one or more groups chosen,independently of each other, from the following atoms or groups:hydroxyl, (C₁-C₆)alkoxy, halogen, cyano, NRaRb, CO—R₅, —CO—NR₆R₇,—CO—O—R₈, —NR₉—CO—R₁₀, an oxido group, a group (C₁-C₆)alkyl, which isitself optionally substituted with one or more hydroxyl or group NRaRb;

the other groups being as defined previously.

Among the compounds that are subjects of the invention, a fourth groupof compounds is constituted by the compounds of formula (I) as definedpreviously, in which:

R₂ represents a pyrrole, furan, thiophene, pyrazole, imidazole,triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole,isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine ortriazine group; optionally substituted with one or more groups chosenfrom the following atoms or groups: hydroxyl, (C₁-C₆)alkoxy, oxido,halogen, —NRaRb, (C₁-C₆)alkyl which is itself optionally substitutedwith a hydroxyl group,

Ra and Rb are, independently of each other, hydrogen or (C₁-C₆)alkyl.

Among the compounds that are subjects of the invention, a fifth group ofcompounds is constituted by the compounds of formula (I) as definedpreviously, in which:

R₂ represents a dioxolane, pyridine, imidazole, pyrazole, triazole,pyrrole, furan, oxazole, imidazoline, thiophene, pyrazine, pyrimidine orthiazole group; optionally substituted with one or more groups chosenfrom the following atoms or groups: hydroxyl, (C₁-C₆)alkoxy, oxido,halogen, —NRaRb, (C₁-C₆)alkyl which is itself optionally substitutedwith a hydroxyl group,

Ra and Rb are, independently of each other, hydrogen or (C₁-C₆)alkyl,

the other groups being as defined previously.

Among the compounds that are subjects of the invention, a sixth group ofcompounds is constituted by the compounds of formula (I) as definedpreviously, in which:

R₂ represents an indole, isoindole, benzimidazole, indazole, indolizine,benzofuran, isobenzofuran, benzothiophene, benzo[c]thiophen,pyrrolopyridine, imidazopyridine, pyrazolopyridine, triazolopyridine,tetrazolopyridine, pyrrolopyrimidine, imidazopyrimidine,pyrazolopyrimidine, triazolopyrimidine, tetrazolopyrimidine,pyrrolopyrazine, imidazopyrazine, pyrazolopyrazine, triazolopyrazine,tetrazolopyrazine, pyrrolopyridazine, imidazopyridazine,pyrazolopyridazine, triazolopyridazine, tetrazolopyridazine,pyrrolotriazine, imidazotriazine, pyrazolotriazine, triazolotriazine,tetrazolotriazine, furopyridine, furopyrimidine, furopyrazine,furopyridazine, furotriazine, oxazolopyridine, oxazolopyrimidine,oxazolopyrazine, oxazolopyridazine, oxazolotriazine, isoxazolopyridine,isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine,isoxazolotriazine, oxadiazolopyridine, oxadiazolopyrimidine,oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolotriazine,benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine,thienopyrimidine, thienopyrazine, thienopyridazine, thienotriazine,thiazolopyridine, thiazolopyrimidine, thiazolopyrazine,thiazolopyridazine, thiazolotriazine, isothiazolopyridine,isothiazolopyrimidine, isothiazolopyrazine, isothiazolopyridazine,isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine,thiadiazolopyrazine, thiadiazolopyridazine, thiadiazolotriazine,benzothiazole, benzoisothiazole or benzothiadiazole group; optionallysubstituted with one or more groups chosen from the following atoms orgroups: hydroxyl, (C₁-C₆)alkoxy, oxido, halogen, —NRaRb, (C₁-C₆)alkylwhich is itself optionally substituted with a hydroxyl group,

Ra and Rb are, independently of each other, hydrogen or (C₁-C₆)alkyl;

the other groups being as defined previously.

Among the compounds that are subjects of the invention, a seventh groupof compounds is constituted by the compounds of formula (I) as definedpreviously, in which:

R₂ represents an indole group optionally substituted with one or moregroups chosen from the following atoms or groups: hydroxyl,(C₁-C₆)alkoxy, oxido, halogen, —NRaRb, (C₁-C₆)alkyl which is itselfoptionally substituted with a hydroxyl group,

Ra and Rb are, independently of each other, hydrogen or (C₁-C₆)alkyl;

the other groups being as defined previously.

Among the compounds that are subjects of the invention, an eighth groupof compounds is constituted by the compounds of formula (I) as definedpreviously, in which:

R₂ represents a dioxolane, pyridine, imidazole, pyrazole, triazole,pyrrole, furan, oxazole, indole, imidazoline, thiophene, pyrazine,pyrimidine or thiazole group, optionally substituted with one or morehydroxyl, methyl, hydroxymethyl, methoxy, oxido, halogen or NH₂ groups,

the other groups being as defined previously.

Among the compounds that are subjects of the invention, a ninth group ofcompounds is constituted by the compounds of formula (I) as definedpreviously, in which R₁ represents a hydrogen atom or a group(C₁-C₆)alkyl;

the other groups being as defined previously.

Among the compounds that are subjects of the invention, a tenth group ofcompounds is constituted by the compounds of formula (I) as definedpreviously, in which R₁ represents a hydrogen atom or a methyl group;

the other groups being as defined previously.

Among the compounds that are subjects of the invention, an eleventhgroup of compounds is constituted by the compounds of formula (I) asdefined previously, in which R₃ and R₄ represent a hydrogen atom;

the other groups being as defined previously.

Among the compounds that are subjects of the invention, a twelfth groupof compounds is constituted by the compounds of formula (I) as definedpreviously, in which:

X represents a phenyl group optionally substituted with one or morefluorine or chlorine atoms or with a cyano group;

R₂ represents a dioxolane, pyridine, imidazole, pyrazole, triazole,pyrrole, furan, oxazole, indole, imidazoline, thiophene, pyrazine,pyrimidine or thiazole group, optionally substituted with one or morehydroxyl, methyl, hydroxymethyl, methoxy, oxido, halogen or NH₂ groups,

R₁ represents a hydrogen atom or a methyl group;

R₃ and R₄ represent a hydrogen atom;

in the form of the base or of an acid-addition salt.

Among the compounds of formula (I) that are subjects of the invention, athirteenth group of compounds is constituted of compounds for which:

X represents a phenyl group optionally substituted with one or morefluorine atoms;

R₂ represents a pyridine, furan, dioxolane, imidazole, pyrazole,triazole, pyrrole, thiazole, oxazole, pyrazine, pyrimidine, thiophene,indole or imidazoline group, these groups being optionally substitutedwith a hydroxymethyl, NH₂, methyl, methoxy, hydroxyl or oxido group or afluorine atom;

R₁ represents a hydrogen atom or a methyl group;

R₃ and R₄ represent a hydrogen atom,

in the form of the base or of an acid-addition salt.

Among the compounds of formula (I) that are subjects of the invention,mention may be made especially of the following compounds:

-   6-(1,3-Dioxolan-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(pyrid-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-[5-(Hydroxymethyl)pyrid-3-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   6-[4-(Hydroxymethyl)pyrid-2-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide    and the hydrochloride (1:1) thereof-   6-(6-Aminopyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide    and the hydrochloride (1:1) thereof-   6-(1H-Imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide    and the hydrochloride (1:1) thereof-   N-Phenyl-6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-(2-Methyl-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   6-(3-Furyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   6-(1H-Imidazol-1-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide    and the trifluoroacetate (1:1) thereof-   6-(Oxazol-5-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   6-(2-Aminothiazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   6-(2-Methyl-1,3-dioxolan-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   6-(4,5-Dihydro-1H-imidazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide    and the hydrochloride (1:1) thereof-   6-(6-Methoxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   5-Methyl-N-phenyl-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-(2-Amino-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide    and the trifluoroacetate (1:1) thereof-   6-(2-Aminothiazol-5-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   6-(6-Hydroxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3,5-Difluorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-(2-Furyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   6-[6-(Hydroxymethyl)pyrid-2-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide    and the hydrochloride (1:1) thereof-   6-(1-Oxidopyrid-3-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide    and the hydrochloride (1:1) thereof-   N-Phenyl-6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-(1H-Imidazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide    hydrochloride (1:1)-   6-(1-Methyl-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   6-(Oxazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   N-(3,5-Difluorophenyl)-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(pyrid-4-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-(1H-Indol-3-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(thiophen-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(pyrazin-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-(1-Oxidopyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(pyrimidin-5-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(thien-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-(5-Fluoro-2-furyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Fluorophenyl)-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,5-Difluorophenyl)-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,3-Difluorophenyl)-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-(6-Aminopyrid-2-yl)-N-(3-fluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-Phenyl-6-(pyrimidin-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-(1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-(2-Aminothiazol-4-yl)-N-(3-fluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3-Fluorophenyl)-6-[5-(hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxamide-   6-[2-(Hydroxymethyl)-1H-imidazol-4-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide-   N-(3,5-Difluorophenyl)-6-(6-methylpyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Chlorophenyl)-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3,5-Difluorophenyl)-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Fluorophenyl)-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,5-Difluorophenyl)-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,3-Difluorophenyl)-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3,5-Difluorophenyl)-6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Fluorophenyl)-6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,5-Difluorophenyl)-6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,3-Difluorophenyl)-6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Chlorophenyl)-6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,5-Difluorophenyl)-6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Chlorophenyl)-6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Fluorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,5-Difluorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,3-Difluorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Chlorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,3-Difluorophenyl)-6-[5-(hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Fluorophenyl)-6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Chlorophenyl)-6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Cyanophenyl)-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   6-(6-Aminopyrid-2-yl)-N-(3,5-difluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide    and the dihydrochloride thereof-   6-(6-Aminopyrid-2-yl)-N-(2-fluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide    and the dihydrochloride thereof-   6-(6-Aminopyrid-2-yl)-N-(2,5-difluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide    and the dihydrochloride thereof-   6-(6-Aminopyrid-2-yl)-N-(2,3-difluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide    and the dihydrochloride thereof-   6-(6-Aminopyrid-2-yl)-N-(2-chlorophenyl)imidazo[1,2-a]pyridine-2-carboxamide    and the dihydrochloride thereof-   N-(2-Chlorophenyl)-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Fluorophenyl)-6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Chlorophenyl)-6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3,5-Difluorophenyl)-6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3,5-Difluorophenyl)-6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Fluorophenyl)-6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,3-Difluorophenyl)-6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3,5-Difluorophenyl)-6-[5-(hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,5-Difluorophenyl)-6-[5-(hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,3-Difluorophenyl)-6-(1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,5-Difluorophenyl)-6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,3-Difluorophenyl)-6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(3,5-Difluorophenyl)-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Fluorophenyl)-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2,5-Difluorophenyl)-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide-   N-(2-Chlorophenyl)-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide;    and the acid-addition salts thereof.

In accordance with the invention, the compounds of general formula (I)may be prepared according to the process described in Scheme 1.

The first synthetic route (transformation A₂) consists in preparing,according to the methods known to those skilled in the art, a2-aminopyridine of formula (II), in which R₁, R₂, R₃ and R₄ are asdefined previously, and then in forming the imidazo[1,2-a]pyridine ringby condensation of a halogenated derivative of 2-oxo-N-arylpropionamide(III) in which Hal represents a chlorine, bromine or iodine atom and Xis as defined previously, by analogy with the methods described by J-J.Bourguignon et al. in Aust. J. Chem., 50, 719 (1997) and by J. G.Lombardino in J. Org. Chem., 30, 2403 (1965), for example.

The halogenated derivatives of 2-oxo-N-arylpropionamide (III) may beobtained, for example, according to the method described by R. Kluger etal. in J. Am. Chem. Soc., 106, 4017 (1984).

The 2-aminopyridines of formula (II), in which R₁, R₂, R₃ and R₄ are asdefined previously, may be prepared, for example, via transformation A₁,i.e.:

-   -   via a coupling reaction of a 2-aminopyridine derivative of        formula (IV), in which R₁, R₃ and R₄ are as defined previously        and Z represents a boryl, stannyl or silyl group, with a        derivative R₂—Z′ (V) in which R₂ is as defined previously, and        Z′ represents a halogen atom such as bromine or iodine or a        sulfonyloxy group,    -   via a coupling reaction of a 2-aminopyridine derivative of        formula (IV), in which R₁, R₃ and R₄ are as defined previously        and Z represents a halogen atom such as bromine or iodine, with        a derivative R₂—Z′ (V) in which R₂ is as defined previously, and        Z′ represents a reactive group such as a boryl, stannyl or silyl        group or a hydrogen atom, or via any other method known to those        skilled in the art.

The second synthetic route (transformation B₂) consists in coupling animidazopyridine-2-carboxylic acid or a derivative thereof of formula(VI), in which R₁, R₂, R₃ and R₄ are as defined previously, Y representsa hydroxyl group, a halogen atom or a group (C₁-C₆)alkoxy, with anarylamine X—NH₂ of formula (VII), in which X is as defined previously,according to methods known to those skilled in the art. Thus, the acidmay be converted beforehand into a reactive derivative thereof such asan acid halide, anhydride, mixed anhydride or activated ester, and thenreacted with the amine (VII) in the presence of a base such asdiisopropylethylamine, triethylamine or pyridine, in an inert solventsuch as THF, DMF or dichloromethane. The coupling may also be performedin the presence of a coupling agent such as CDI, EDCI, HATU or HBTUunder the same conditions without isolating the reactive intermediate.Alternatively, the amine (VII) may be reacted with an ester of the acidof formula (VI) in the presence of a catalyst such as trimethylaluminiumaccording to the method of Weinreb, S. et al. (Tet. Lett. (1977), 18,4171), or zirconium tert-butoxide.

The imidazopyridine-2-carboxylic acid derivatives of formula (VI), inwhich R₁, R₂, R₃ and R₄ are as defined previously and Y is(C₁-C₆)alkoxy, hydroxyl or halogen, are prepared by condensation of a2-aminopyridine of formula (II), in which R₁, R₂, R₃ and R₄ are asdefined previously, with a 3-halo-2-oxopropionic acid of formula (VIII)in which Hal represents a halogen and Y is (C₁-C₆)alkoxy, underconditions similar to those used for the condensation of a derivative offormula (II) with a derivative of formula (III), followed, whereappropriate, by conversion of the ester to the acid and then to the acidchloride or another reactive derivative (transformation B₁).

The third synthetic route (transformation C₂) consists in coupling aderivative of general formula (IX), in which R₁, R₃, R₄ and X are asdefined previously and Z represents a halogen atom such as bromine oriodine, a sulfonyloxy group or a reactive group such as boryl, stannylor silyl, with a derivative of formula R₂—Z′ (V) in which R₂ is asdefined previously, and

-   -   Z′ represents a reactive group such as a boryl, stannyl or silyl        group or a hydrogen atom when Z represents a halogen atom or a        sulfonyloxy group, or    -   Z′ represents a halogen atom such as bromine or iodine when Z        represents a reactive group such as a boryl, stannyl or silyl        group or a hydrogen atom.

The derivatives of general formula (IX) in which R₁, R₃, R₄, X and Z areas defined previously may be prepared:

-   -   by condensation of a 2-aminopyridine of formula (IV), in which        R₁, R₃, R₄ and Z are as defined previously, with a        2-oxo-N-arylpropionamide derivative (III) in which Hal        represents a chlorine, bromine or iodine atom and X is as        defined previously (transformation C₁), according to methods        mentioned for the conversion of a compound of formula (II) into        a compound of formula (I) or    -   by amidation of an imidazopyridine-2-carboxylic acid or a        derivative thereof of formula (X), in which R₁, R₂, R₃ and R₄        are as defined previously, Y represents a hydroxyl group, a        halogen atom or a group (C₁-C₆)alkoxy, with an arylamine X—NH₂        of formula (VII), in which X is as defined previously        (transformation D₂), according to methods mentioned for the        conversion of a compound of formula (VI) into a compound of        formula (I).

The imidazopyridine-2-carboxylic acids or derivatives thereof of formula(X), in which R₁, R₃ and R₄ are as defined previously, Y is(C₁-C₆)alkoxy, hydroxyl or halogen and Z represents a boryl, stannyl orsilyl group or a halogen atom, may be prepared (transformation D₁) bycondensation of a 2-aminopyridine of formula (IV), in which R₁, R₃ andR₄ are as defined previously and Z represents a boryl, stannyl or silylgroup or a halogen atom, with a 3-halo-2-oxopropionic acid ester offormula (VIII), in which Hal represents a halogen and Y is(C₁-C₆)alkoxy, under conditions similar to those mentioned previouslyfor the condensation of the 2-aminopyridines of formula (II), with aderivative of formula (VIII) to obtain the imidazopyridine-2-carboxylicacids or derivatives thereof of formula (VI), according totransformation B₁, followed, where appropriate, by conversion of theester to the acid and then to the acid chloride or another reactivederivative.

The imidazopyridine-2-carboxylic acids or derivatives thereof of formula(VI), in which R₁, R₂, R₃ and R₄ are as defined previously and Y is(C₁-C₆)alkoxy, hydroxyl or halogen, may also be prepared (transformationE₁) by coupling a derivative of general formula (X), in which R₁, R₃,and R₄ are as defined previously, Y is (C₁-C₆)alkoxy and Z represents ahalogen atom such as bromine or iodine, a sulfonyloxy group or areactive group such as boryl, stannyl or silyl, with a derivative offormula R₂—Z′ (V), in which R₂ is as defined previously, and

-   -   Z′ represents a reactive group such as a boryl, stannyl or silyl        group or a hydrogen atom when Z represents a halogen atom or a        sulfonyloxy group, or    -   Z′ represents a halogen atom such as bromine or iodine when Z        represents a reactive group such as a boryl, stannyl or silyl        group or a hydrogen atom,        followed, where appropriate, by conversion of the ester to the        acid and then to the acid chloride or another reactive        derivative.

The coupling of the derivatives of formula (IV), (IX) or (X) with theproducts of formula (V) may be performed via any method known to thoseskilled in the art, in particular by working in the presence ofcopper-based or palladium-based catalysts, or ligands such asphosphines, according to or by analogy with the methods described, forexample, in the following references and cited references:

-   -   for the reactions of Suzuki type: N. Miyaura, A. Suzuki, Chem.        Rev., 95, 2457, (1995),    -   for the reactions of Stille type: V. Farina et al., Org. React.,        50, 1 (1997),    -   for the reactions of Hiyama type: T. Hiyama et al., Top. Curr.        Chem., 2002, 219, 61 (2002),    -   for the reactions of Negishi type: E. Negishi et al., Chem.        Rev., 103, 1979 (2003),    -   for the reactions of Bettina type: M. Miura et al., Chem. Lett.,        200 (2007).

It is also possible, in order to perform the coupling, to form asintermediates, but without isolating them, organometallic derivativessuch as zinc derivatives.

In accordance with the invention, the compounds of general formulae (I),(VI) and (II) may also be prepared according to the processes describedin Scheme 2.

This synthetic route consists in converting a compound of generalformula (XI), (XII) or (XIII), in which R₁, R₃, R₄, X and Y are asdefined previously and W represents a precursor group allowing theconstruction of the heterocycle of formula R₂, according to the methodsknown to those skilled in the art.

By way of example, W may represent:

-   -   a 2-haloacyl group such as bromoacetyl, or a 1-halo-2-oxoalkyl        group such as 1-bromo-2-oxoethyl, which may be converted, for        example, into a thiazolyl, imidazolyl or oxazolyl group by        treatment with thiourea, thioamide, guanidine, urea or amide        derivatives,    -   an alkynyl group, such as ethynyl, which may be converted into a        1,2,3-triazol-4-yl group,    -   an acyl group such as formyl, which may be converted, for        example, into a 1,3-dioxolanyl-2 or oxazolyl group,    -   a cyano group, which may be converted, for example, into a        dihydroimidazolyl(2) or 1,3,4-triazol-2-yl group.

The compounds of general formula (XI) may be obtained from the compoundsof formula (XII) under the conditions described for the preparation ofthe compounds (I), from imidazopyridine-2-carboxylic acid derivatives offormula (VI) via the transformations B₂.

The imidazopyridine-2-carboxylic acid derivatives of general formula(XII) may be obtained from the aminopyridines of formula (XIII), underthe conditions described for the conversion of the aminopyridines offormula (II) into compounds of general formula (I), via transformationA₂.

The products of formula (I) and the precursors thereof of formula (II),(IV), (VI), (IX) or (X), may be subjected, if desired and if necessary,in order to obtain products of formula (I) or to be converted into otherproducts of formula (I), to one or more of the following transformationreactions, in any order:

a) a reaction for the esterification or amidation of an acid function,b) a reaction for the amidation of an amine function,c) a reaction for the hydrolysis of an ester function to an acidfunction,d) a reaction for the transformation of a hydroxyl function into analkoxy function,e) a reaction for the oxidation of an alcohol function to an aldehyde orketone function,f) a reaction for the transformation of aldehyde or ketone functionsinto an alcohol function, via reduction or the action of anorganometallic agent such as an organomagnesium reagent,g) a reaction for the transformation of a nitrile radical into analdehyde function,h) a reaction for the transformation of a nitrile radical into a ketonefunction,i) a reaction for the oxidation of an alkenyl group to an aldehyde orketone function,j) a reaction for the catalytic coupling of an organometallic derivativesuch as a boron, tin or silicon derivative with a halogenated derivativein order to introduce an alkyl, alkenyl, alkynyl, aryl or heteroarylsubstituent,k) a reaction for the conversion of a primary or secondary amino groupinto a secondary or tertiary amino group via reductive amination oralkylation,l) a reaction for the conversion of a halogenated derivative into asecondary or tertiary amino group via substitution—optionallycatalytic—with a primary or secondary amine,m) a reaction for the protection of reactive functions,n) a reaction for the removal of the protecting groups that may be borneby protected reactive functions,o) a reaction for salification with a mineral or organic acid or with abase to obtain the corresponding salt,p) a reaction for the resolution of racemic forms into enantiomers,the said products of formula (I) thus obtained being, where appropriate,in any possible isomeric form: racemic mixtures, enantiomers anddiastereoisomers.

In Schemes 1 and 2, the starting materials and the reagents, when theirmode of preparation is not described, are commercially available ordescribed in the literature, or may be prepared according to methodsthat are described therein or that are known to those skilled in theart.

The examples that follow describe the preparation of certain compoundsin accordance with the invention. These examples are not limiting, andserve merely to illustrate the present invention. The numbers of theillustrated compounds refer to those given in the table hereinbelow,which illustrates the chemical structures and the physical properties ofa number of compounds according to the invention.

EXAMPLE 16-(1,3-Dioxolan-2-yl)-N-phenylimidazol[1,2-a]pyridine-2-carboxamide

To a solution of 137 mg of6-formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 8)in 5 mL of toluene are added 45 μL of ethylene glycol, 169 mg ofpara-toluenesulfonic acid and molecular sieves. The mixture is refluxedfor 24 hours in a round-bottomed flask equipped with Dean-Starkapparatus, and then cooled, filtered, diluted with 100 mL ofdichloromethane and washed with 2N sodium hydroxide and with water. Theorganic phases are dried and concentrated to dryness to give a mixtureof the starting material and of the expected product, which isredissolved in 5 mL of methanol containing 410 μL of ethylene glycol,130 mg of para-toluenesulfonic acid and molecular sieves. The mixture isheated for 16 hours at reflux and then cooled, filtered and concentratedto dryness. The residue is chromatographed on a silica cartridge,eluting with a 70/30 mixture of dichloromethane and ethyl acetate togive 53 mg of6-(1,3-dioxolan-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide inthe form of a white solid.

EXAMPLE 2 N-Phenyl-6-(pyrid-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

150 mg of 6-bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 1), 0.237 g of pyridine-3-boronic acid, 45 mg oftetrakis(triphenylphosphine)palladium, 2 mL of aqueous 2M sodiumcarbonate solution, 4 mL of acetonitrile and 4 mL of toluene are placedin a microwave tube. The mixture is heated for 20 minutes in a microwavemachine set at 150° C., and then cooled and filtered, the insolublematter being washed with a mixture of methanol and dichloromethane. Thecombined filtrates are concentrated to dryness under reduced pressure.The residue is concreted with aqueous methanol to give 73 mg ofN-phenyl-6-(pyrid-3-yl)imidazo[1,2-a]pyridine-2-carboxamide in the formof an off-white solid.

EXAMPLE 3 N-Phenyl-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide

230 mg of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 2), 690 mg of 2-tributylstannylpyridine, 120 mg oftetrakis(triphenylphosphine)palladium and 4 mL of N,N-dimethylformamideare placed in a microwave tube. The reaction mixture is heated for 5minutes in a microwave machine set at 100° C., and then for 5 minutes at150° C. and concentrated to dryness. The residue is chromatographed on asilica cartridge, eluting with a mixture of dichloromethane and ethylacetate. The fractions containing the expected product are combined andevaporated to dryness under reduced pressure to give 56 mg ofN-phenyl-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide in the formof a white solid.

EXAMPLE 46-[5-(Hydroxymethyl)pyrid-3-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

163 mg of6-trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 4), 310 mg of (5-bromopyrid-3-yl)methanol, 66 mg oftetrakis(triphenylphosphine)-palladium and 4 mL of N,N-dimethylformamideare placed in a microwave tube. The reaction mixture is heated for 20minutes in a microwave machine set at 150° C. and concentrated todryness. The residue is chromatographed on a silica cartridge, elutingwith dichloromethane. The fractions containing the expected product arecombined and evaporated to dryness under reduced pressure to give 61 mgof6-[5-(hydroxymethyl)pyrid-3-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamidein the form of a white solid.

EXAMPLE 56-[4-(Hydroxymethyl)pyrid-2-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochloride (1:1) 5.16-[4-(Hydroxymethyl)pyrid-2-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

This product is obtained in a manner similar to that of Example 4,replacing the (5-bromopyrid-3-yl)methanol with(2-bromopyrid-4-yl)methanol.

5.26-[4-(Hydroxymethyl)pyrid-2-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochloride (1:1)

A suspension of 117 mg of6-[4-(hydroxymethyl)pyrid-2-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamidein 2 mL of methanol is treated with 0.68 mL of aqueous 0.5 Nhydrochloric acid solution. The mixture is stirred for 16 hours at roomtemperature and then evaporated to dryness under reduced pressure. Thesolid obtained is triturated in methanol, filtered off and dried to give91 mg of6-[4-(hydroxymethyl)pyrid-2-yl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochloride (1:1).

EXAMPLE 66-(6-Aminopyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochloride (1:1)

236 mg of6-trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 4), 413 mg of 6-bromopyrid-2-ylamine, 95 mg oftetrakis(triphenylphosphine)palladium and 4 mL, of N,N-dimethylformamideare placed in a microwave tube. The reaction mixture is heated for 45minutes in a microwave machine set at 150° C. and concentrated todryness. The residue is chromatographed on a silica cartridge, elutingwith a mixture of dichloromethane and ethyl acetate. The fractionscontaining the expected product are combined and evaporated to drynessunder reduced pressure to give 147 mg of6-(6-aminopyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide inthe form of a yellow solid, which product is taken up in a mixture ofdioxane and methanol and treated with 112 μL of a 4 M solution ofhydrogen chloride in dioxane. After stirring for 1 hour at roomtemperature, the precipitate is filtered off by suction, washed withdioxane and dried to give 156 mg of6-(6-aminopyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochloride (1:1) in the form of a pale yellow solid.

EXAMPLE 76-(1H-Imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochloride (1:1) 7.1:6-(1-Triphenylmethyl-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

540 mg ofN-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide(Intermediate 5), 13 mL of dioxane, 6.8 mL of 2M sodium carbonatesolution, 843 mg of 4-iodo-1-triphenylmethylimidazole and 86 mg oftetrakis(triphenylphosphine)-palladium are placed in a microwave tube.The mixture is heated for 10 minutes in a microwave machine set at 120°C., and then cooled and concentrated under reduced pressure. The residueis taken up in 100 mL of dichloromethane. After washing with water, theorganic phase is dried over magnesium sulfate and concentrated todryness under reduced pressure. The residue is chromatographed on asilica cartridge, eluting with a gradient of cyclohexane and ethylacetate (from 100/0 to 60/40). The fractions containing the expectedproduct are combined and concentrated to dryness under reduced pressure.The solid is crystallized from acetonitrile. The crystals are washedwith acetonitrile and then with ethyl ether and then dried under vacuumto give 342 mg of6-(1-triphenylmethyl-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidein the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.09 (t, J=7.5 Hz, 1H), 7.19 (d,J=8.0 Hz, 6H), 7.33 (t, J=7.5 Hz, 2H), from 7.38 to 7.49 (m, 9H), 7.53(d, J=1.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.59 (d, J=9.5 Hz, 1H), 7.79(dd, J=1.5 and 9.5 Hz, 1H), 7.89 (d, J=7.5 Hz, 2H), 8.50 (s, 1H), 9.03(broad s, 1H), 10.2 (s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 546 [M+H]⁺.

7.2: 6-(1H-Imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochloride (1:1)

A suspension of 270 mg of6-(1-triphenylmethyl-1H-imidazol-4-yl)-N-phenyl-imidazo[1,2-a]pyridine-2-carboxamidein 4 mL of 2N hydrochloric acid is heated for 30 minutes at 70° C. andthen diluted with 2 mL of methanol, heated for 45 minutes at reflux,diluted again by addition of 2 mL of dichloromethane and heated for afurther 2 hours at reflux. The reaction mixture is stirred for 60 hoursat room temperature. The precipitate is filtered off by suction, washedwith methanol, water and then pentane and dried under reduced pressureto give 96 mg of6-(1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochloride (1:1) in the form of a white solid.

EXAMPLE 8N-Phenyl-6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

300 mg of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 2), 4 mL of dioxane, 4 mL of water, 185 mg of1H-pyrazole-3-boronic acid, 45 mg of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and 1.077 g ofcaesium carbonate are placed in a microwave tube. The mixture is heatedfor 20 minutes in a microwave machine set at 160° C., and then cooled,diluted with 20 mL of water and extracted twice with 20 mL ofdichloromethane. The combined organic phases are dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure.The residue is chromatographed on a silica cartridge, eluting with agradient of dichloromethane and methanol (from 0 to 10%). The fractionscontaining the expected product are combined and concentrated to drynessunder reduced pressure to give 40 mg ofN-phenyl-6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide in theform of a white solid.

EXAMPLE 9N-Phenyl-6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

250 mg of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 2), 8 mL of N,N-dimethylformamide, 7.7 mg of palladiumacetate, 197 mg of cuprous iodide and 71.3 mg of 1,2,4-triazole areplaced in a microwave tube. The reaction mixture is heated for 2.5 hoursin a microwave machine set at 200° C. The cooled reaction mixture isfiltered, the insoluble matter is rinsed with N,N-dimethylformamide,dichloromethane and methanol and the combined filtrates are concentratedto dryness under reduced pressure. The residue is chromatographed on asilica cartridge, eluting with a 90/10 mixture of dichloromethane andmethanol. The fractions containing the pure expected product arecombined and evaporated to dryness under reduced pressure to give 40 mgofN-phenyl-6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamidein the form of a white solid.

EXAMPLE 10N-Phenyl-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide 10.1:N-Phenyl-6-(1-triisopropylsilyl-1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

This product is obtained in a manner similar to that of Example 8,replacing the 1H-pyrazole-3-boronic acid with1-triisopropylsilyl-1H-pyrrol-3-boronic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.09 (d, J=7.5 Hz, 18H), 1.56 (m,3H), 6.66 (broad s, 1H), 6.95 (t, J=2.0 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H),7.33 (t, J=7.5 Hz, 2H), 7.39 (broad s, 1H), 7.61 (d, J=9.5 Hz, 1H), 7.73(dd, J=1.5 and 9.5 Hz, 1H), 7.89 (d, J=7.5 Hz, 2H), 8.39 (s, 1H), 8.82(broad s, 1H), 10.15 (s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 459 [M+H]⁺

10.2: N-Phenyl-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

A solution of 120 mg ofN-phenyl-6-(1-triisopropylsilyl-1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamidein 5 mL of tetrahydrofuran is treated with 262 μL of a molar solution oftetrabutylammonium fluoride in tetrahydrofuran, and stirred for 10minutes at room temperature. It is then diluted with 15 mL ofdichloromethane and 20 mL of water. The organic phase is dried andconcentrated to dryness under reduced pressure. The residue is taken upin 2 mL of dichloromethane, and the solid filtered off is washed twicewith 1 mL of dichloromethane and then twice with 1 mL of diisopropylether, triturated twice with 2 mL of water, filtered off by suction andwashed again with 2 mL of dichloromethane and 2 mL of diisopropyl etherand then dried to give 40 mg ofN-phenyl-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide in theform of a white solid

EXAMPLE 116-(2-Methyl-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

400 mg of6-trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 4), 229 mg of 2-methyl-4-iodo-1H-imidazole, 8 mL oftetrahydrofuran, 9.1 mg of bis(dibenzylideneacetone)palladium and 4.6 mgof tris(2-furyl)phosphine are placed in a microwave tube. The reactionmixture is heated for 50 minutes in a microwave machine set at 130° C.and then concentrated to dryness. The residue is taken up in 3.5 mL ofN,N-dimethylformamide and a further 150 mg of2-methyl-4-iodo-1H-imidazole, 10 mg ofbis(dibenzylideneacetone)palladium and 5 mg of tris(2-furyl)phosphineare added, followed by heating again for 40 minutes in a microwavemachine set at 120° C. The reaction mixture is filtered, the insolublematter is rinsed with methanol and dichloromethane and the combinedfiltrates are concentrated under reduced pressure. The residue ischromatographed on a silica cartridge, eluting with dichloromethane andthen with a 90/10 mixture of dichloromethane and methanol. The fractionscontaining the pure expected product are combined and evaporated todryness under reduced pressure to give 28 mg of6-(2-methyl-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidein the form of a beige-coloured solid.

EXAMPLE 12 6-(3-Furyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

200 mg of 6-bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 1), 10 mL of dioxane, 400 μL of 3-(triethoxysilyl)furan,42 mg of palladium acetate, 42 mg of 1,4-diazabicyclo(2.2.2)octane(DABCO) and 1.5 mL of a molar solution of tetrabutylammonium fluoride intetrahydrofuran are placed in a microwave tube. The reaction mixture isheated for 3 hours in a microwave machine set at 120° C., 200 μL of3-(triethoxysilyl)furan, 20 mg of palladium acetate and 20 mg of DABCOare then added and the mixture is heated for a further 1.5 hours in amicrowave machine set at 150° C. and then cooled and filtered. Thefiltrate is concentrated to dryness under reduced pressure and theresidue is chromatographed on a silica cartridge, eluting withdichloromethane. The fractions containing the pure expected product arecombined and evaporated to dryness under reduced pressure. The solid isdissolved while hot in a mixture of dichloromethane and methanol. Thehot solution is filtered and treated with diisopropyl ether. Theprecipitate formed is filtered off by suction and dried to give 25 mg of6-(3-furyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form ofa yellow solid.

EXAMPLE 136-(1H-Imidazol-1-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidetrifluoroacetate (1:1)

A mixture of 0.6 g of6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2), 20mL of N,N-dimethylformamide, 1.08 g of caesium carbonate, 113 mg ofimidazole, 60 mg of 1,10-phenanthroline and 31.5 mg of cuprous iodide isheated for 21 hours at 130° C. and, after addition of 70 mg ofimidazole, is reacted for a further 3 hours at the same temperature andfor 64 hours at room temperature. The reaction mixture is filtered, theinsoluble matter is rinsed with dichloromethane and the combinedfiltrates are concentrated under reduced pressure. The residue ispurified by preparative HPLC on a Waters Sunfire 30×100, 5 μm column,eluting with a gradient of acetonitrile containing from 0 to 60% waterand 0.07% trifluoroacetic acid over 15 minutes and with a flow rate of30 mL/min. The fractions containing the pure expected product arecombined and evaporated to dryness under reduced pressure. The solid isbeaten in 2 mL of methanol, filtered off and washed with 1 mL ofmethanol, and dried to give 110 mg of6-(1H-imidazol-1-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidetrifluoroacetate (1:1) in the form of a beige-coloured solid.

EXAMPLE 14 6-(Oxazol-5-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

To a suspension of 200 mg of6-formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 8)in 10 mL of methanol are added 104 mg of potassium carbonate and 147 mgof para-toluenesulfonylmethylisonitrile (TOSMIC). The reaction mixtureis refluxed for 2 hours and then evaporated to dryness under reducedpressure, taken up in 300 mL of dichloromethane and washed with water.The organic phase is dried and concentrated to dryness on silica andthen chromatographed on a silica cartridge, eluting with a gradient offrom 0 to 20% of methanol in dichloromethane. The fractions containingthe expected product are concentrated to dryness and the solid obtainedis triturated with a small amount of dichloromethane, filtered off anddried to give 80 mg of6-(oxazol-5-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the formof a white solid.

EXAMPLE 156-(2-Aminothiazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

To a suspension of 60 mg of crude6-(2-bromoacetyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 10 mLof methanol are added 14 mg of thiourea. The reaction mixture is heatedfor 45 minutes at reflux and then concentrated to dryness under reducedpressure. The residue is chromatographed on a silica cartridge, elutingwith a mixture of dichloromethane and methanol (gradient of from 100/0to 90/10). The fractions containing the expected product are combinedand evaporated to dryness under reduced pressure to give 20 mg of6-(2-aminothiazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide inthe form of a white solid.

EXAMPLE 166-(2-Methyl-1,3-dioxolan-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

A mixture of 80 mg of6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 2.5 mLof toluene, 280 μL of ethylene glycol and 170 mg of para-toluenesulfonicacid is placed over molecular sieves. The mixture is refluxed for 2hours and then cooled, filtered and diluted with 20 mL ofdichloromethane and 20 mL of water, and neutralized with 2N sodiumhydroxide solution. The aqueous phase is washed with dichloromethane andthe combined organic phases are dried and concentrated to dryness. Theresidue is chromatographed on a silica cartridge, eluting with agradient of dichloromethane and ethyl acetate of from 0/30 to 70/30 togive 17 mg of6-(2-methyl-1,3-dioxolan-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidein the form of a white solid.

EXAMPLE 176-(4,5-Dihydro-1H-imidazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochlorides (1:1) and (1:2) 17.1 Ethyl2-phenylcarbamoylimidazo[1,2-a]pyridine-6-carboximidate hydrochloride(1:1)

A suspension of 300 mg ofN-phenyl-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2) in25 mL of ethanol containing 0.5 mL of DMF is cooled to 0° C. and thentreated for 1 hour 40 minutes with hydrogen chloride gas. The reactionmixture is stirred at room temperature for 16 hours and thenconcentrated under reduced pressure to a small volume. The precipitateis filtered off by suction and washed with ethanol and ethyl ether togive 296 mg of ethyl2-phenylcarbamoylimidazo[1,2-a]pyridine-6-carboximidate hydrochloride(1:1) in the form of a white solid, which is used without furtherpurification for the rest of the synthesis.

17.26-(4,5-Dihydro-1H-imidazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochlorides (1:1) and (1:2)

A suspension of 296 mg of ethyl2-phenylcarbamoylimidazo[1,2-a]pyridine-6-carboximidate hydrochloride(1:1) in 10 mL of ethanol is cooled to 0° C., followed by addition of144 μL of ethylenediamine. The reaction mixture is refluxed for 16 hoursand then stirred at room temperature for 60 hours. The precipitate isfiltered off by suction and washed with ethanol and then recrystallizedfrom methanol to give 64 mg of6-(4,5-dihydro-1H-imidazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochloride (1:2) in the form of a white solid. The filtrate isconcentrated to dryness and taken up in water. The insoluble matter isfiltered off by suction, washed with methanol and then dried to give 99mg of6-(4,5-dihydro-1H-imidazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidehydrochloride (1:1) in the form of a white solid.

EXAMPLE 186-(6-Methoxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of 624 mg of caesium carbonate, 90 mg of2-bromo-6-methoxypyridine and 17.5 mg of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium in 10 mL ofdioxane and 4 mL of water are added 160 mg of2-phenylcarbamoylimidazo[1,2-a]pyridine-6-boronic acid. The mixture isrefluxed for one hour, and then cooled and concentrated to dryness underreduced pressure. The residue is taken up in 150 mL of dichloromethaneand washed with 100 mL of water. The organic phase is dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure on silica and then chromatographed on a silica cartridge,eluting with a gradient of from 0 to 35% ethyl acetate in cyclohexane.The fractions containing the pure expected product are combined andconcentrated to dryness under reduced pressure to give 36 mg of6-(6-methoxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide inthe form of an off-white solid.

EXAMPLE 195-Methyl-N-phenyl-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide19.1: Ethyl6-iodo-5-methyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate

To a suspension of 2 g of 5-iodo-6-methylpyridine-2-amine in 15 mL ofdimethoxyethane are added 1.3 mL of ethyl bromopyruvate. The reactionmixture is stirred at 20° C. for 16 hours and then concentrated todryness, taken up in 15 mL of ethanol, refluxed for 2.5 hours andfinally concentrated under reduced pressure. The residue is taken up ina mixture of dichloromethane and saturated sodium bicarbonate solution.The organic phase is dried over magnesium sulfate and concentrated todryness under reduced pressure to give 2.77 g of ethyl6-iodo-5-methyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate in theform of a beige-coloured solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.33 (t, J=7.1 Hz, 3H), 2.84 (s,3H), 4.33 (q, J=7.1 Hz, 2H), 7.34 (d, J=9.3 Hz, 1H), 7.66 (d, J=9.3 Hz,1H), 8.48 (s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 331 [M+H]+.

19.2:6-Iodo-5-methyl-N-phenyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide

To a solution of 852 μL of aniline in 104 mL of toluene cooled to 0° C.are added dropwise 6.2 mL of a 2M solution of trimethylaluminium intoluene, followed by addition, at 20° C., of 1.5 g of ethyl6-iodo-5-methyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate. Thereaction mixture is stirred for 2 hours at 20° C. The resulting mixtureis cooled to 4° C. and 120 mL of saturated ammonium chloride solutionare then added. After concentrating under reduced pressure, the residueis taken up in ethyl acetate and the organic phase is washed with water,dried over magnesium sulfate, filtered through Celite and evaporated todryness under reduced pressure. The residue is triturated in methanol,filtered off and dried to give 1.15 g of6-iodo-5-methyl-N-phenyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamidein the form of a yellow solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 2.89 (s, 3H), 7.10 (tt, J=1.5 and7.5 Hz, 1H), 7.33 (t, J=7.5 Hz, 2H), 7.39 (d, J=9.5 Hz, 1H), 7.70 (d,J=9.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 2H), 8.49 (s, 1H), 10.3 (s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 378 [M+H]⁺.

19.3:5-Methyl-N-phenyl-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide

This product is obtained in a manner similar to that for the product ofExample 3, replacing the6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide with6-iodo-5-methyl-N-phenyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide.

EXAMPLE 206-(2-Amino-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]-pyridine-2-carboxamidetrifluoroacetate (1:1)

To a solution of 135 mg of6-(2-bromoacetyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 9) in 10 mL of N,N-dimethylformamide are added 190 mg of1-tert-butyloxycarbonylguanidine. The reaction mixture is stirred for 16hours at 20° C. and then concentrated to dryness at 60° C. under reducedpressure. The residue is taken up in 5 mL of dichloromethane and 3 mL ofmethanol and the solution is evaporated on silica and thenchromatographed on a silica cartridge, eluting with a mixture ofdichloromethane and methanol (gradient of from 100/0 to 90/10). Thefractions containing the expected product are combined and evaporated todryness under reduced pressure to give 50 mg of a mixture of6-(2-tert-butyloxycarbonylaminothiazol-4-A-N-phenylimidazo[1,2-a]pyridine-2-carboxamideand6-(2-amino-1-tert-butyloxycarbonylthiazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidein the form of a beige-coloured solid. This product is dissolved in 5 mLof dioxane and treated with 320 μL of a 4 N solution of hydrogenchloride in dioxane. The mixture is heated at 60° C. for 4 hours,followed by addition of 200 μL of a 4 N solution of hydrogen chloride indioxane, and then concentrated to dryness under reduced pressure. Theresidue is purified by preparative LC/MS to give 18 mg of6-(2-amino-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidetrifluoroacetate (1:1) in the form of a beige-coloured solid.

EXAMPLE 216-(2-Aminothiazol-5-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide21.1: 6-(2-Ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

This product is obtained under conditions similar to those described inthe first step of preparation of Intermediate 9, replacing thetributyl(1-ethoxyvinyl)tin with tributyl(2-ethoxyvinyl)tin.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.33 (t, J=7.2 Hz, 3H), 4.06 (q,J=7.2 Hz, 2H), 5.26 (d, J=6.8 Hz, 1H), 6.52 (d, J=6.8 Hz, 1H), 7.08 (t,J=7.8 Hz, 1H), 7.34 (t, J=7.8 Hz, 2H), 7.54-7.66 (m, 2H), 7.88 (d, J=7.8Hz, 2H), 8.51 (s, 1H), 8.75 (s, 1H), 10.16 (s, 1H).

21.2:6-(2-Aminothiazol-5-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of 168 mg of6-(2-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 5.1 mLof tetrahydrofuran are added 1.4 mL of water followed by addition, aftercooling to 0° C., of a solution of 97 mg of N-bromosuccinimide in 0.7 mLof tetrahydrofuran. The reaction mixture is stirred for 3 hours at roomtemperature. The6-(1-bromo-2-oxoethyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamideformed is not isolated from the reaction mixture, which is treated with42 mg of thiourea and stirred for a further 16 hours after allowing thetemperature to return to 20° C. The solid formed is filtered off bysuction, washed with water and then with methanol and dried to give 51mg of6-(2-aminothiazol-5-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide inthe form of a white solid.

EXAMPLE 226-(6-Hydroxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide22.1:6-(6-Benzyloxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of 250 mg of 2-benzyloxy-6-bromopyridine in 12 mL ofdioxane are added a solution of 1.234 g of caesium carbonate in 3 mL ofwater, 34.6 mg of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and then 546 mgofN-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamidehydrobromide (1:1). The mixture is heated at 110° C. for 2 hours 45minutes, and then cooled and filtered. The solid is washed with a smallamount of methanol and then with dichloromethane and is then taken up in250 mL of boiling methanol containing 5 mL of trifluoroacetic acid. Theinsoluble matter is filtered off and washed with methanol and then withdichloromethane and the filtrate is concentrated to dryness underreduced pressure. The residue is chromatographed on a silica cartridge,eluting with a gradient of from 0 to 5% of methanol in dichloromethane.The fractions containing the pure expected product are combined andconcentrated to dryness under reduced pressure to give 0.3 g of6-(6-benzyloxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidein the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 5.54 (s, 2H), 6.91 (d, J=8.3 Hz,1H), 7.11 (broad t, J=7.7 Hz, 1H), 7.31-7.45 (m, 5H), 7.54 (m, 2H), 7.63(d, J=7.8 Hz, 1H), 7.77 (d, J=9.7 Hz, 1H), 7.85-7.93 (m, 3H), 8.12 (dd,J=9.7, 2.0 Hz, 1H), 8.64 (s, 1H), 9.44 (broad s, 1H), 10.30 (broad s,1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 421 [M+H]⁺.

22.2:6-(6-Hydroxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

A solution of 300 mg of6-(6-benzyloxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamidein 3 mL of trifluoroacetic acid is stirred at 25° C. for 48 hours andthen evaporated to dryness under reduced pressure at 45° C. The residueis triturated with ether, filtered off and dried, and then trituratedagain with 2 mL of saturated sodium bicarbonate solution, washed twicewith 2 mL of water and twice with 2 mL of ethyl ether and dried underreduced pressure to give 168 mg of6-(6-hydroxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide inthe form of a beige-coloured solid.

EXAMPLE 23N-Phenyl-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide23.1 6-Ethynyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

0.2 g of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 2), 156 μL of trimethylsilylacetylene, 20 mg ofdichlorobis(triphenylphosphine)palladium and 2 mL of piperidine areplaced in a 20 mL microwave tube. The mixture is heated for 15 minutesin a microwave machine set at 130° C. After cooling, the mixture ispoured into 50 mL of saturated aqueous ammonium chloride solution. Theresulting mixture is extracted twice with 70 mL of ethyl ether. Thecombined organic phases are separated out by settling, dried andconcentrated to dryness under reduced pressure. The residue is taken upin 4 mL of a 1M solution of tetrabutylammonium fluoride in THF andstirred for 16 hours at 25° C. After evaporating the reaction medium todryness, the residue is chromatographed on silica, eluting with amixture of cyclohexane and ethyl acetate (gradient from 0 to 35%) togive 30 mg of 6-ethynyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide inthe form of a beige-coloured solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 4.37 (s, 1H), 7.09 (t, J=8.0 Hz,1H), 7.34 (broad t, J=8.0 Hz, 2H), 7.39 (broad d, J=9.5 Hz, 1H), 7.67(d, J=9.5 Hz, 1H), 7.89 (broad d, J=8.0 Hz, 2H), 8.48 (s, 1H), 8.92(broad s, 1H), 10.3 (s, 1H).

Mass spectrum (EI): m/z 261 [M]⁺(base peak), m/z=221 [M-NHPh]⁺.

23.2:N-Phenyl-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

123 mg of 6-ethynyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 46 mgof sodium azide, 38 mg of ammonium chloride and 5 mL ofN,N-dimethylformamide are placed in a microwave tube. The reactionmixture is heated for 20 minutes in a microwave machine set at 170° C.and then for a further 30 minutes under the same conditions, followed byaddition of 46 mg of sodium azide and 38 mg of ammonium chloride, andfinally concentrated at 50° C. under reduced pressure. The residue istaken up in 20 mL of ethyl acetate and 20 mL of water. The aqueous phaseis extracted twice with 20 mL of ethyl acetate and the combined organicphases are washed with 30 mL of saturated brine and then dried overmagnesium sulfate and concentrated to dryness under reduced pressure.The residue is chromatographed on a silica cartridge, eluting with agradient of dichloromethane and methanol (from 100/0 to 90/10). Thefractions containing the expected product are combined and concentratedto dryness under reduced pressure to give 36 mg ofN-phenyl-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamidein the form of an off-white solid.

EXAMPLE 24N-(3,5-Difluorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

83 mg of potassium carbonate and 4 mL of 1,2-dimethoxyethane are placedin a microwave tube, followed, after degassing with argon, by 120 mg ofN-(3,5-difluorophenyl)-6-iodoimidazo[1,2-a]pyridine-2-carboxamide(Intermediate 10), 40 mg of 3-furanboronic acid and 21 mg ofdichlorobis(triphenylphosphine)palladium(II). The reaction mixture isheated for 20 minutes in a microwave machine set at 120° C. and thenpoured into a mixture of 15 mL of ethyl acetate and 15 mL of water. Theaqueous phase is extracted twice with 15 mL of ethyl acetate and thecombined organic phases are washed with 15 mL of saturated brine andthen dried over magnesium sulfate and concentrated to dryness underreduced pressure. The residue is triturated twice with 10 mL of amethanol/ethyl ether mixture (1/1) and then washed with isopropanol andpentane and dried to give 22 mg ofN-(3,5-difluorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxamidein the form of a white solid.

EXAMPLE 25N-(3-Fluorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

To a suspension of 65 mg of6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid (Intermediate 19)and 104 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride in 2 mL of anhydrous pyridine, placed under argon, areadded 68 mg of 3-fluoroaniline. The reaction mixture is stirred for 16hours at 80° C. and then concentrated to dryness under reduced pressure.The residue is taken up in dichloromethane and washed with water. Theorganic phase is dried over magnesium sulfate and concentrated todryness under reduced pressure to give 46 mg ofN-(3-fluorophenyl)-6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide inthe form of a white solid.

The intermediates described below are useful for preparing the compoundsof the present invention.

Intermediate 1 6-Bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of 3 g of aniline in 366 mL of toluene cooled to 0° C. areadded dropwise 22.5 mL of a 2M solution of trimethylaluminium intoluene, followed by addition, at 20° C., of 5.6 g of ethyl6-bromoimidazo[1,2-a]pyridine-2-carboxylate. The reaction mixture isstirred for 2 hours at room temperature. The resulting mixture is cooledto 4° C. and 150 mL of saturated ammonium chloride solution are thenadded. The reaction mixture is concentrated to dryness and is then takenup in 400 mL of water and 400 mL of dichloromethane. The organic phaseis dried over magnesium sulfate, filtered through Celite and evaporatedto dryness under reduced pressure to give 4.6 g of6-bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of anoff-white powder.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.09 (t, J=7.5 Hz, 1H), 7.34 (t,J=7.5 Hz, 2H), 7.51 (d, J=9.5 Hz, 1H), 7.57 (dd, J=1.5 and 9.5 Hz, 1H),7.88 (d, J=8.0 Hz, 2H), 8.42 (s, 1H), 9.02 (broad s, 1H), 10.25 (s, 1H).

Mass spectrum (EI): m/z=363 [M]⁺, m/z=271 [M-C₆H₆N]⁺, m/z=144[m/z=271-I]⁺.

Intermediate 2 6-Iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

By working in the same manner as for the preparation of Intermediate 1,replacing the ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate withethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate,6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide is obtained in theform of a beige-coloured solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.09 (t, J=7.5 Hz, 1H), 7.34 (t,J=7.5 Hz, 2H), 7.51 (d, J=9.5 Hz, 1H), 7.57 (dd, J=1.5 and 9.5 Hz, 1H),7.88 (d, J=8.0 Hz, 2H), 8.42 (s, 1H), 9.02 (broad s, 1H), 10.25 (s, 1H).

Mass spectrum (EI): m/z=363 [M]⁺, m/z=271 [M-C₆H₆N]⁺, m/z=144[m/z=271-I]⁺.

Intermediate 3 N-Phenyl-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide

By working in the same manner as for the preparation of Intermediate 1,replacing the ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate withethyl 6-cyanoimidazo[1,2-a]pyridine-2-carboxylate (J. Med. Chem. (1998),41(22), 4317), N-phenyl-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide isobtained in the form of a yellow solid

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.11 (t, J=7.5 Hz, 1H), 7.35 (t,J=7.5 Hz, 2H), 7.65 (dd, J=2.0 and 9.5 Hz, 1H), 7.81 (d, J=9.5 Hz, 1H),7.89 (d, J=8.0 Hz, 2H), 8.58 (s, 1H), 9.41 (broad s, 1H), 10.4 (broad s,1H)

IR spectrum (KBr): 3364; 2234; 1671; 1599; 1560; 1527; 1504; 1433 and748 cm⁻¹

Mass spectrum (EI): m/z=262 [M]⁺(base peak), m/z=170 [M-C₆H₆N]⁺, m/z=143[m/z=170-HCN]⁺.

Intermediate 46-Trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

To a suspension of 160 mg of6-bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 10 mL of toleneare added 260 μL of hexamethyldistannane and 30 mg oftetrakis-(triphenylphosphine)palladium(0). The reaction mixture isheated for 2 hours at reflux and then stirred for 16 hours at roomtemperature and filtered through a pad of Celite. The filtrate isconcentrated under reduced pressure and the residue is chromatographedon a silica cartridge, eluting with dichloromethane. The fractionscontaining the expected product are combined and evaporated to drynessunder reduced pressure to give 163 mg of6-trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in theform of a yellow solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 0.85 (m, 9H), 7.09 (t, J=7.5 Hz,1H), 7.33 (t, J=7.5 Hz, 2H), 7.40 (broad d, J=9.5 Hz, 1H), 7.61 (broadd, J=9.5 Hz, 1H), 7.89 (d, J=7.5 Hz, 2H), 8.43 (s, 1H), 8.53 (m, 1H),10.2 (s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 402, [M+H]⁺

Intermediate 5N-Phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo-[1,2-a]pyridine-2-carboxamideand the hydrobromide (1:1) thereof

To a solution of 1 g of 3-bromo-2-oxo-N-phenylpropionamide in 50 mL of1,2-dimethoxyethane are added 1.09 g of2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. Thereaction mixture is stirred for 40 hours at room temperature and thenconcentrated to dryness under reduced pressure. The residue is taken upin 30 mL of ethanol and refluxed for 90 minutes. After concentrating todryness under reduced pressure, the solid is triturated in a smallamount of ethanol, filtered off and washed with ethanol and then withethyl ether to give 0.6 g ofN-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamidehydrobromide (1:1) in the form of a white solid.

This hydrobromide is taken up in 200 mL of ethyl acetate and washed withsaturated sodium bicarbonate solution. The organic phase is dried andconcentrated to dryness under reduced pressure to give 0.53 g ofN-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamidein the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.33 (s, 12H), 7.10 (t, J=7.5 Hz,1H), 7.34 (t, J=7.5 Hz, 2H), 7.46 (dd, J=1.5 and 9.5 Hz, 1H), 7.63 (d,J=9.5 Hz, 1H), 7.89 (d, J=7.5 Hz, 2H), 8.58 (s, 1H), 8.96 (broad s, 1H),10.25 (s, 1H).

Mass spectrum (EI): m/z 363 [M]⁺; m/z 271=[M-NHPh]⁺; m/z171=[271-C6H12O]⁻.

Intermediate 6 2-Phenylcarbamoylimidazo[1,2-a]pyridine-6-boronic acidhydrochloride (1:1)

1°) To a solution of 0.8 g of 3-bromo-2-oxo-N-phenylpropionamide in 30mL of 1,2-dimethoxyethane is added 0.87 g of2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. Thereaction mixture is stirred for 16 hours at room temperature and thenconcentrated to dryness under reduced pressure. The residue is taken upin 15 mL of ethanol and refluxed for 2 hours. After concentrating todryness under reduced pressure, the residue is crystallized fromethanol, filtered off by suction and washed with ethanol and then withethyl ether to give 0.75 g ofN-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamidehydrobromide (1:1) in the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.34 (s, 12H), 7.11 (t, J=7.8 Hz,1H), 7.35 (t, J=7.8 Hz, 2H), 7.54 (broad d, J=9.3 Hz, 1H), 7.66 (d,J=9.3 Hz, 1H), 7.87 (d, J=7.8 Hz, 2H), 8.63 (s, 1H), 9.02 (s, 1H), 10.37(broad s, 1H).

Mass spectrum (EI): m/z 363 [M]⁺.

2°) A solution of 0.19 g ofN-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamidehydrobromide (1:1) in 9 mL of acetonitrile is treated with 0.5 mL ofhydrochloric acid and 1 g of polymer-supported benzeneboronic acid(Alfa-Aesar L19459, ˜3 mmol/g). The reaction mixture is stirred for 16hours at 25° C. and then refluxed for 1 hour. The resin is filtered off,washed with acetonitrile and then with methanol and the combinedfiltrates are evaporated to dryness under reduced pressure to give 160mg of 2-phenylcarbamoylimidazo[1,2-a]pyridine-6-boronic acidhydrochloride (1:1) in the form of an orange-coloured solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.14 (t, J=7.8 Hz, 1H), 7.38 (t,J=7.8 Hz, 2H), 7.72 (broad m, 1H), 7.85 (d, J=7.8 Hz, 2H), 7.93 (broadm, 1H), 7.94-8.63 (very broad m, 2H), 8.81 (broad m, 1H), 9.04 (broad m,1H), 10.52 (broad m, 1H).

Intermediate 7 N-Phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide

A mixture of 0.73 g of6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 209 mg oftetrakis(triphenylphosphine)palladium(0), 587 μL of tributylvinyltin and17 mL of DMF is heated for 10 minutes at 130° C. in a microwave machineand then concentrated to dryness. The residue is taken up in 100 mL ofwater and extracted with twice 70 mL of ethyl acetate. The combinedorganic phases are washed with saturated sodium chloride solution, driedover magnesium sulfate and evaporated to dryness under reduced pressure.The solid is triturated in ethyl acetate, filtered off by suction,washed with ethyl acetate and then with isopropyl ether, and taken up ina mixture of methanol and dichloromethane. The insoluble matter isfiltered off and washed with methanol. The filtrate is concentrated todryness under reduced pressure to give 0.29 g ofN-phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide in the form of awhite solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 5.39 (d, J=11.0 Hz, 1H), 5.92 (d,J=17.5 Hz, 1H), 6.77 (dd, J=11.0 and 17.5 Hz, 1H), 7.09 (broad t, J=7.5Hz, 1H), 7.34 (broad t, J=7.5 Hz, 2H), 7.64 (d, J=9.5 Hz, 1H), 7.70 (dd,J=2.0 and 9.5 Hz, 1H), 7.89 (broad d, J=8.0 Hz, 2H), 8.47 (s, 1H), 8.66(broad s, 1H), 10.2 (s, 1H).

Mass spectrum (EI): m/z 263 [M⁺]

Intermediate 8 6-Formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

A suspension of 150 mg ofN-phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide, 232 μL of osmiumtetroxide and 167.5 mg of sodium periodate in a mixture of 6 mL of THF,3 mL of t-butanol and 3 mL of water is stirred for 20 hours at 20° C.and then for a further 48 hours while adding in four portions 100 μL ofosmium tetroxide and 80 mg of sodium periodate. The reaction mixture ispoured into 50 mL of water and the resulting mixture is extracted twicewith 50 mL of ethyl acetate. The combined organic phases are washed withsaturated aqueous sodium chloride solution, separated by settling, driedand concentrated to dryness under reduced pressure. The residue ischromatographed on silica, eluting with a mixture of cyclohexane andethyl acetate (gradient from 0 to 50%) to give 100 mg of6-formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of awhite solid

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.11 (t, J=8.0 Hz, 1H), 7.36 (broadt, J=8.0 Hz, 2H), 7.71 (dd, J=1.5 and 9.5 Hz, 1H), 7.77 (broad d, J=9.5Hz, 1H), 7.90 (broad d, J=8.0 Hz, 2H), 8.73 (s, 1H), 9.39 (broad s, 1H),10.0 (s, 1H), 10.35 (broad s, 1H).

Mass spectrum (LC/MS): m/z 266, [M+H⁺]

Intermediate 96-(2-Bromoacetyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide 9.1:6-(1-Ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

To a suspension of 1 g of6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 50 mL of tolueneare added 159 mg of tetrakis(triphenylphosphine)palladium and 1.09 g oftributyl(1-ethoxyvinyl)tin. The reaction mixture is heated for 9 hoursat 150° C. and then for 16 hours at 130° C., and concentrated todryness. The residue is taken up in dichloromethane and washed withaqueous 10% potassium fluoride solution. The organic phase is dried andconcentrated to dryness and the residue is chromatographed on a silicacartridge, eluting with a mixture of cyclohexane and ethyl acetate. Thefractions containing the expected product are combined and evaporated todryness under reduced pressure to give 0.52 g of6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in theform of a beige-coloured solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.40 (t, J=7.0 Hz, 3H), 3.97 (q,J=7.0 Hz, 2H), 4.46 (d, J=3.0 Hz, 1H), 4.90 (d, J=3.0 Hz, 1H), 7.09 (t,J=8.0 Hz, 1H), 7.34 (broad t, J=8.0 Hz, 2H), 7.61 (d, J=9.5 Hz, 1H),7.66 (dd, J=2.0 and 9.5 Hz, 1H), 7.89 (broad d, J=8.0 Hz, 2H), 8.57 (s,1H), 8.83 (broad s, 1H), 10.2 (s, 1H).

9.2: 6-(2-Bromoacetyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of 123 mg of6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 4 mLof tetrahydrofuran are added 1 mL of water and then, after cooling to 0°C., 71 mg of N-bromosuccinimide. The reaction mixture is stirred for 2.5hours at room temperature and then diluted with 80 mL ofdichloromethane. The organic phase is washed with water and then driedand concentrated to dryness under reduced pressure to give 60 mg ofcrude 6-(2-bromoacetyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide inthe form of a white solid (containing small amounts of 6-acetylderivative and dibromo derivative) that is used without furtherpurification.

¹H NMR spectrum (DMSO-d6, δ in ppm): 4.92 (s, 2H), 7.11 (t, J=7.5 Hz,1H), 7.36 (t, J=7.5 Hz, 2H), 7.75 (d, J=9.5 Hz, 1H), 7.82 (dd, J=1.5 and9.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 2H), 8.61 (s, 1H), 9.57 (broad s, 1H),10.35 (s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 358 [M+H]⁺, m/z 356 [M−H]⁻.

Intermediate 10N-(3,5-difluorophenyl)-6-iodoimidazo[1,2-a]pyridine-2-carboxamide

To a solution of 980 mg of aniline in 100 mL of toluene cooled to 0° C.are added dropwise 5 mL of a 2M solution of trimethylaluminium intoluene and then, at 20° C., 1.5 g of ethyl6-iodoimidazo[1,2-a]pyridine-2-carboxylate. The reaction mixture isstirred for 2 hours at 20° C. The resulting mixture is cooled to 4° C.and 100 mL of saturated ammonium chloride solution are then added. Afterconcentrating under reduced pressure, the residue is taken up in ethylacetate and the organic phase is washed with water, dried over magnesiumsulfate, filtered through Celite and evaporated to dryness under reducedpressure. The residue is triturated in ethyl ether, filtered off anddried to give 258 mg ofN-(3,5-difluorophenyl)-6-iodoimidazo[1,2-a]pyridine-2-carboxamide in theform of a yellow solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 6.92 (tt, J=2.0 and 9.0 Hz, 1H),7.51 (d, J=9.5 Hz, 1H), 7.59 (dd, J=1.5 and 9.5 Hz, 1H), 7.72 (m, 2H),8.47 (s, 1H), 9.02 (broad s, 1H), 10.75 (s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 398 [M+H]⁻; m/z 400 [M+H]⁺.

Intermediate 116-(6-{[(1,1-Dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo-[1,2-a]pyridine-2-carboxylicacid 11.1: Ethyl6-(6-aminopyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate

350 mg of 2-amino-6-bromopyridine, 750 mg of2-ethoxycarbonylimidazo[1,2-a]pyridine-6-boronic acid and 57 mg of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium are degassedunder vacuum and then suspended, under argon, in 20 mL of degasseddioxane. After addition of 2 mL of aqueous 2N sodium carbonate solution,the mixture is degassed under vacuum, placed under argon and heated for5 hours at 90° C., and then cooled, diluted and stirred in a mixture of50 mL of saturated sodium bicarbonate solution and 50 mL ofdichloromethane. The organic phase is dried over sodium sulfate,filtered and concentrated to dryness under reduced pressure. The residueis chromatographed on silica, eluting with a mixture of ethyl acetateand hexane. The fractions containing the expected product are combinedand concentrated to dryness under reduced pressure to give 446 mg ofethyl 6-(6-aminopyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.13 (dd, J=1.0, 1.6 1H), 8.61 (d,J=0.7, 1H), 7.94 (dd, J=1.8, 9.6, 1H), 7.65 (d, J=9.6, 1H), 7.50 (t,J=8.1, 1H), 7.07 (d, J=7.0, 1H), 6.48 (dd, J=0.3, 8.1, 1H), 6.08 (broads, 2H), 4.33 (q, J=7.1, 2H), 1.33 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=283 [M+H]⁺.

11.2: Ethyl6-(6-{[(1,1-dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylateand ethyl6-(6-{bis[(1,1-dimethylethoxy)carbonyl]amino}pyrid-2-yl)-imidazo[1,2-a]pyridine-2-carboxylate

To a suspension of 700 mg of ethyl6-(6-aminopyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate and 25 mg of4-dimethylaminopyridine in 5 mL of acetonitrile are added 1.14 mL ofdi-tert-butyl dicarbonate. The mixture is stirred for 16 hours at 25° C.and then concentrated. The residue is chromatographed on silica, elutingwith gradient of ethyl acetate and hexane (from 50/50 to 100/0) to give370 mg of ethyl6-(6-{bis[(1,1-dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.23 (s, 1H), 8.65 (s, 1H),8.06-7.98 (m, 2H), 7.95 (d, J=7.7, 1H), 7.76 (d, J=9.6, 1H), 7.43 (d,J=7.8, 1H), 4.33 (q, J=7.0, 2H), 1.43 (s, 18H), 1.34 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=483 [M+H]⁺,

and 163 mg of ethyl6-(6-{[(1,1-dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.28 (s, 1H), 8.50 (s, 1H),8.04-8.00 (m, 2H), 7.95 (d, J=7.8, 1H), 7.70 (d, J=9.6, 1H), 7.38 (d,J=7.9, 1H), 4.31 (q, J=7.0, 2H), 1.39 (s, 9H), 1.33 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=383 [M+H]⁺.

11.3:6-(6-{[(1,1-Dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylicacid

0.9 mL of aqueous 2 M lithium hydroxide solution is added to a solutionof 292 mg of ethyl6-(6-{bis[(1,1-dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylatein 4.73 mL of a 50/1 mixture of tetrahydrofuran and methanol. Thereaction mixture is stirred for 7 hours at 25° C. and then treateddropwise at 0° C. with 2 N hydrochloric acid HCl until a pH of 3 isobtained. The precipitate formed after 20 minutes is filtered off bysuction and washed with water (20 mL) and diethyl ether (20 ml) and thendried under reduced pressure to give 195 mg of6-(6-{[(1,1-dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylicacid in the form of a beige-coloured solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 13.5-12.0 (br, 1H), 9.80 (s, 1H),9.24 (s, 1H), 8.51 (s, 1H), 8.03 (dd, J=1.5, 9.6 1H), 7.88 (app, t,J=8.0, 7.8, 1H), 7.77 (d, J=8.2, 1H), 7.73 (d, J=9.6, 1H), 7.62 (d,J=7.5, 1H), 1.50 (s, 9H)

Intermediate 12 6-(Pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid12.1: Ethyl (6-pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate

A mixture of 3.18 g of caesium carbonate, 25 mL of dioxane, 9.3 mL ofwater, 500 mg of 2-iodopyridine, 89 mg of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and 848 mg ofethyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxylatehydrobromide (1:1) is heated for 2 hours at 110° C., and then partiallyconcentrated, diluted with dichloromethane and filtered. The organicphase is washed with water and dried over magnesium sulfate, filteredand concentrated to dryness under reduced pressure. The residue ischromatographed on a silica cartridge, eluting with a mixture ofdichloromethane and cyclohexane (80/20). The fractions containing theexpected product are combined and concentrated to dryness under reducedpressure to give 317 mg of ethyl6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate in the form of abrown oil.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.34 (t, J=7.0 Hz, 3H), 4.33 (q,J=7.0 Hz, 2H), 7.42 (ddd, J=7.5, 5.5, 2.0 Hz, 1H), 7.73 (d, J=9.3 Hz,1H), 7.85-8.02 (m, 2H), 8.07 (dd, J=9.3, 2.0 Hz, 1H), 8.64 (s, 1H), 8.70(broad d, J=5.5 Hz, 1H), 9.36 (broad s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 268 [M+H]⁺.

12.2: 6-(Pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

317 mg of ethyl 6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate aresaponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3) to give 280 mg of6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid in the form of apasty pink solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.47 (m, 1H), 7.83 (d, J=9.8 Hz,1H), 7.99 (dt, J=8.5, 2.0 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 8.31 (broadd, J=9.8 Hz, 1H), 8.73 (m, 2H), 9.52 (broad s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 240 [M+H]⁺.

Intermediate 136-(1-Triphenylmethyl-1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylicacid 13.1: Ethyl6-(1-triphenylmethyl-1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate

873 mg of 4-iodo-1-triphenylmethylimidazole, 750 mg of2-ethoxycarbonylimidazo[1,2-a]pyridine-6-boronic acid, 23 mg ofpalladium acetate and 70 mg of (2-biphenyl)dicyclohexyl-phosphine aredegassed under vacuum and then suspended, under argon, in a degassedmixture of 15 mL of toluene, 5 mL of water and 5 mL ofN-methylpyrrolidone. After addition of 950 mg of potassium phosphate,the mixture is degassed under vacuum and then placed under argon andheated for 15 minutes at 100° C. by microwave, then cooled, diluted andstirred in a mixture of 50 mL of saturated sodium bicarbonate solutionand 50 mL of dichloromethane. The organic phase is dried over sodiumsulfate, filtered and concentrated to dryness under reduced pressure.The residue is chromatographed on silica, eluting with a mixture ofethyl acetate and hexane. The fractions containing the expected productare combined and concentrated to dryness under reduced pressure to give508 mg of ethyl6-(1-triphenylmethyl-1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.97 (s, 1H), 8.54 (s, 1H),7.76-7.72 (m, 1H), 7.56-7.52 (m, 3H), 7.47-7.37 (m, 9H), 7.20-7.17 (m,6H), 4.31-4.27 (m, 2H), 1.34-1.20 (m, 3H).

Mass spectrum (APCI): m/z=499 [M+H]⁺.

13.2:6-(1-Triphenylmethyl-1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylicacid

500 mg of ethyl6-(1-triphenylmethyl-1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylateare saponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3) to give 346 mg of6-(1-triphenylmethyl-1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylicacid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.01 (s, 1H), 8.51 (s, 1H), 7.83(d, J=9.5, 1H), 7.59-7.56 (m, 3H), 7.47-7.37 (m, 9H), 7.20-7.17 (m, 6H).No exchangeable proton is observed.

Mass spectrum (APCI): m/z=471 [M+H]⁺.

Intermediate 146-(2-{[(1,1-Dimethylethoxy)carbonyl]amino}thiazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylicacid 14.1: Ethyl6-(2-{[(1,1-dimethylethoxy)carbonyl]amino}thiazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate

465 mg of tert-butyl 4-iodothiazol-2-ylcarbamate, 434 mg of2-ethoxycarbonyl-imidazo[1,2-a]pyridine-6-boronic acid and 104 mg of[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium are degassedunder vacuum. After addition of 10 mL of degassed tetrahydrofuran and0.66 mL of aqueous 2N sodium carbonate solution, the reaction mixture isheated for 2 hours at 100° C. and then cooled, diluted withdichloromethane and washed with aqueous half-saturated sodiumbicarbonate solution. The organic phase is dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure. The residueis chromatographed on silica, eluting with a dichloromethane/methanolmixture (99:1 to 99:2). The fractions containing the expected productare combined and concentrated to dryness under reduced pressure. Thesolid obtained is washed with 5 mL of diethyl ether to give 125 mg ofethyl6-(2-{[(1,1-dimethylethoxy)carbonyl]amino}thiazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylatein the form of an off-white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 11.65 (s, 1H), 8.84 (s, 1H), 8.47(s, 1H), 7.84 (s, 1H), 7.68-7.71 (m, 2H), 4.32 (q, J=7.1, 2H), 1.51 (s,9H), 1.33 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=389 [M+H]⁺.

14.2:6-(2-{[(1,1-Dimethylethoxy)carbonyl]amino}thiazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylicacid

125 mg of ethyl6-(2-{[(1,1-dimethylethoxy)carbonyl]amino}thiazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylateare saponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3), to give 90 mg of6-(2-{[(1,1-dimethylethoxy)carbonyl]amino}thiazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylicacid in the form of a brown solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 11.66 (s, 1H), 8.86 (s, 1H), 8.42(s, 1H), 7.84 (s, 1H), 7.67-7.69 (m, 2H), 1.51 (s, 9H).

Mass spectrum (APCI): m/z=361 [M+H]⁺.

Intermediate 15 6-(1H-Pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxylicacid 15.1 Ethyl6-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]imidazo[1,2-a]pyridine-2-carboxylate

100 mg of ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate, 135 mg of1-(triisopropyl-silyl)pyrrole-3-boronic acid and 18 mg oftetrakis(triphenylphosphine)palladium(0) are degassed under vacuum andthen suspended, under argon, in a degassed mixture of 1.5 mL of1,2-dimethoxyethane, 1.5 mL of ethanol and 316 μL of aqueous 2N sodiumcarbonate solution. The reaction mixture is refluxed for 4 hours andthen cooled, diluted and stirred with a mixture of 5 mL of aqueoushalf-saturated sodium bicarbonate solution and 5 mL of dichloromethane.The organic phase is dried over sodium sulfate, filtered andconcentrated to dryness under reduced pressure. The residue ischromatographed on silica, eluting with a mixture of ethyl acetate andhexane (50/50). The fractions containing the expected product arecombined and concentrated to dryness under reduced pressure to give 121mg of ethyl6-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]imidazo[1,2-a]pyridine-2-carboxylate.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.76 (s, 1H), 8.42 (s, 1H), 7.70(dd, J=1.9, 9.7 1H), 7.59 (d, J=9.7 1H), 7.37 (broad s, 1H), 6.94 (m,1H), 6.63 (m, 1H), 4.33 (q, J=6.9, 2H), 1.61-1.50 (m, 3H), 1.33 (t,J=6.9, 3H), 1.10-1.03 (m, 18H).

Mass spectrum (APCI): m/z=412 [M+H]⁺.

15.2: 6-(1H-Pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acidhydrochloride (1:1)

292 mg of ethyl6-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]imidazo[1,2-a]pyridine-2-carboxylateare saponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3), to give 140 mg of6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride(1:1) in the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 11.07 (broad s, 1H), 8.73 (s, 1H),8.39 (s, 1H), 7.69 (dd, J=1.3, 9.5, 1H), 7.59 (d, J=9.5, 1H), 7.31 (s,1H), 6.86 (s, 1H), 6.46 (s, 1H).

Mass spectrum (APCI): m/z=228 [M+H]⁺.

Intermediate 16 6-(1H-Pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylicacid 16.1: Ethyl 6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate

This product is prepared under conditions similar to those described forthe preparation of Intermediate 15 (step 15.1), replacing the1-(triisopropylsilyl)pyrrole-3-boronic acid with pyrazole-3-boronicacid.

¹H NMR spectrum (MeOD-d4, δ in ppm): 8.89 (t, J=1.2, 2.4, 1H), 8.45 (d,J=0.6, 1H), 7.89 (d, J=9.0, 1H), 7.76 (broad s, 1H), 7.67 (d, J=9.5,1H), 6.77 (d, J=2.4, 1H), 4.42 (q, J=7.1, 2H), 1.43 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=257 [M+H]⁺.

16.2: 6-(1H-Pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

128 mg of ethyl 6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylateare saponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3) to give 113 mg of6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 13.50-12.50 (broad s, 1H), 9.03 (s,1H), 8.40 (s, 1H), 7.83-7.80 (m, 2H), 7.63 (d, J=9.4, 1H), 6.74 (s, 1H).

Intermediate 17 6-(1H-Pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylicacid 17.1: Ethyl 6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate

This product is prepared under conditions similar to those described forthe preparation of Intermediate 15 (step 15.1), replacing the1-(triisopropylsilyl)pyrrole-3-boronic acid with pyrazole-4-boronic acidand heating at 90° C. by microwave for 37 minutes.

¹H NMR spectrum (DMSO-d6, δ in ppm): 13.10 (broad s, 1H), 8.83 (s, 1H),8.43 (s, 1H), 8.25 (broad s, 1H), 7.94 (broad s, 1H), 7.69-7.61 (m, 2H),4.31 (q, J=7.1, 2H), 1.32 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=257 [M+H]⁺.

17.2: 6-(1H-Pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

128 mg of ethyl 6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylateare saponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3), to give 60 mg of6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 14.0-12.0 (broad s, 1H), 8.84 (s,1H), 8.36 (s, 1H), 8.10 (s, 2H), 7.64 (s, 2H).

Intermediate 18 6-(Furan-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid18.1: Ethyl 6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxylate

This product is prepared under conditions similar to those described forthe preparation of Intermediate 15 (step 15.1), replacing the1-(triisopropylsilyl)pyrrole-3-boronic acid with furan-2-boronic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.78 (s, 1H), 8.44 (s, 1H), 7.72(dd, J=1.8, 9.6, 1H), 7.63-7.60 (m, 2H), 6.89 (d, J=3.4, 1H), 6.57 (dd,J=1.8, 3.4, 1H), 4.42 (q, J=7.1, 2H), 1.42 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=257 [M+H]⁺.

18.2: 6-(Furan-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

384 mg of ethyl 6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxylate aresaponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3) to give 256 mg of6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.86 (s, 1H), 8.38 (s, 1H), 7.80(dd, J=1.7, 9.5, 1H), 7.67-7.64 (m, 2H), 6.90 (d, J=3.4, 1H), 6.60 (dd,J=1.8, 3.4, 1H).

Intermediate 19 6-(Furan-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid19.1: Ethyl 6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxylate

This product is prepared under conditions similar to those described forthe preparation of Intermediate 15 (step 15.1), replacing the1-(triisopropylsilyl)pyrrole-3-boronic acid with furan-3-boronic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.86 (s, 1H), 8.45 (s, 1H), 8.28(s, 1H), 7.82 (s, 1H), 7.66 (s, 2H), 6.95 (s, 1H), 4.31 (q, J=7.1, 2H),1.33 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=257 [M+H]⁺.

19.2: 6-(Furan-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

384 mg of ethyl 6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxylate aresaponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3) to give 287 mg of6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.86 (s, 1H), 8.38 (s, 1H), 8.27(s, 1H), 7.81 (s, 1H), 7.64 (s, 2H), 6.95 (s, 1H).

Mass spectrum (APCI): m/z=229 [M+H]⁺.

Intermediate 206-[5-(Hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxylic acid20.1: Ethyl 6-(5-formylfuran-2-yl)imidazo[1,2-a]pyridine-2-carboxylate

2 g of ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate, 1.42 g of5-formylfuran-2-boronic acid and 231 mg of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium are degassedunder vacuum and then suspended, under argon, in a degassed mixture of30 mL of dioxane and 9.4 mL of aqueous 2N sodium carbonate solution. Thereaction mixture is heated for 5 hours at 90° C., and then stirred for16 hours at 20° C. and concentrated to dryness. The residue ischromatographed on silica, eluting with a mixture of ethyl acetate andhexane (90/10), with ethyl acetate and then with a mixture (99/1) ofethyl acetate and methanol. The fractions containing the expectedproduct are combined and concentrated to dryness under reduced pressureto give 884 mg of ethyl6-(5-formylfuran-2-yl)imidazo[1,2-a]pyridine-2-carboxylate.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.64 (s, 1H), 9.20 (s, 1H), 8.66(s, 1H), 7.86-7.74 (m, 2H), 7.72 (d, J=3.8, 1H), 7.37 (d, J=3.8, 1H),4.33 (q, J=7.0, 2H), 1.33 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=285 [M+H]⁺.

20.2: Ethyl6-[5-(hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxylate

To a suspension of 770 mg of ethyl6-(5-formylfuran-2-yl)imidazo[1,2-a]pyridine-2-carboxylate in 15 mL ofethanol are added 123 mg of sodium borohydride. The reaction mixture isstirred at 25° C. for 90 minutes and then diluted and stirred with 10 mLof dichloromethane and 3 mL of aqueous half-saturated sodium carbonatesolution. The organic phase is separated out, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residueis chromatographed on silica, eluting with a mixture of dichloromethaneand methanol (98/2). The fractions containing the expected product arecombined and concentrated to dryness under reduced pressure. The solidobtained is triturated in 5 mL of dichloromethane, filtered off anddried to give 403 mg of ethyl6-(5-formylfuran-2-yl)imidazo[1,2-a]pyridine-2-carboxylate in the formof a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.89 (s, 1H), 8.60 (s, 1H), 7.70(m, 2H), 6.98 (d, J=3.3, 1H), 6.45 (d, J=3.3, 1H), 5.30 (t, J=5.3, 1H),4.47 (d, J=5.6, 2H), 4.32 (q; J=7.1, 2H), 1.32 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=287 [M+H]⁺.

20.3: 6-[5-(Hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxylicacid

400 mg of ethyl6-[5-(hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxylate aresaponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3) to give 346 mg of6-[5-(hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxylic acidin the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.06 (s, 1H), 8.73 (s, 1H), 8.03(d, J=9.5, 1H), 7.82 (d, J=9.5, 1H), 7.09 (d, J=3.3, 1H), 6.49 (d,J=3.2, 1H), 4.49 (s, 2H).

Mass spectrum (APCI): m/z=259 [M+H]⁺.

Intermediate 21 6-(Thiophen-3-yl)imidazo[1,2-a]pyridine-2-carboxylicacid 21.1: Ethyl 6-(thiophen-3-yl)imidazo[1,2-a]pyridine-2-carboxylate

This product is prepared under conditions similar to those described forthe preparation of Intermediate 15 (step 15.1), replacing the1-(triisopropylsilyl)pyrrole-3-boronic acid with thiophene-3-boronicacid (catalyst: dichlorobis(triphenylphosphine)palladium).

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.34 (d, J=7.1 Hz, 3H), 4.32 (q,J=7.1 Hz, 2H), 7.56 (dd, J=5.0, 1.4 Hz, 1H), 7.68 (d, J=9.8 Hz, 1H),7.73 (dd, J=5.0, 3.0 Hz, 1H), 7.78 (dd, J=9.8, 1.8 Hz, 1H), 7.97 (dd,J=3.0, 1.4 Hz, 1H), 8.48 (s, 1H), 8.98 (broad s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 273 [M+H]⁺.

21.2: 6-(Thiophen-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

310 mg of ethyl 6-(thiophen-3-yl)imidazo[1,2-a]pyridine-2-carboxylateare saponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3) to give 250 mg of6-(thiophen-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 7.57 (d, J=5.4 Hz, 1H), 7.66 (d,J=9.8 Hz, 1H), 7.73 (dd, J=5.4, 2.8 Hz, 1H), 7.76 (dd, J=9.8, 2.0 Hz,1H), 7.97 (broad d, J=2.0 Hz, 1H), 8.41 (s, 1H), 8.99 (broad s, 1H).

Mass spectrum (LC-MS-DAD-ELSD): m/z 245 [M+H]⁺.

Intermediate 22 6-(Oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid22.1: Ethyl 6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxylate

1 g of ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate, 350 mg oftetrakis(triphenyl-phosphine)palladium(0) and 360 mg of lithium chlorideare degassed under vacuum and then suspended, under argon, in 15 mL ofdegassed dioxane. After addition of 5 g of2-(tri-n-butylstannyl)oxazole, the reaction mixture is heated at 90° C.for 3.5 hours and then cooled, diluted and stirred with a mixture of 100mL of aqueous 1M potassium fluoride solution and 200 mL of ethylacetate. The aqueous phase is extracted with 200 mL of ethyl acetate andthe combined organic phases are washed with brine and dried over sodiumsulfate, filtered and concentrated to dryness under reduced pressure.The residue is chromatographed on silica, eluting with a gradient ofethyl acetate and hexane (from 80/20 to 100/0). The fractions containingthe expected product are combined and concentrated to dryness underreduced pressure to give 530 mg of ethyl6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxylate in the form of ayellow powder.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.30 (d, J=0.8, 1H), 8.68 (s, 1H),8.30 (s, 1H), 7.85 (dd, J=1.7, 9.5, 1H), 7.79 (d, J=9.5, 1H), 7.44 (d,J=0.6, 1H), 4.33 (q, J=7.0, 2H), 1.33 (t, J=7.1, 3H).

Mass spectrum (APCI): m/z=258 [M+H]⁺.

22.2: 6-(Oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

512 mg of ethyl 6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxylate aresaponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3) to give 365 mg of6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid in the form of awhite solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.41 (s, 1H), 8.73 (s, 1H), 8.34(s, 1H), 8.05 (dd, J=1.5, 9.5, 1H), 7.86 (d, J=9.5, 1H), 7.48 (s, 1H).

Intermediate 236-(1H-1,2,4-Triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid 23.1:Ethyl 6-[ethoxy(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate

470 mg of sodium ethanethiolate are added to a solution of 1 g of ethyl6-cyanoimidazo[1,2-a]pyridine-2-carboxylate (J. Med. Chem. (1998),41(22), 4317) in a mixture of 15 mL of ethanol and 10 mL ofdichloromethane cooled to 0° C. The reaction mixture is stirred for 5hours at 25° C. and filtered, and the filtrate is evaporated to dryness.The residue is chromatographed on silica, eluting with a mixture ofdichloromethane and methanol (98/2) to give 625 mg of ethyl6-[ethoxy(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate in the formof a pale yellow solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 9.17 (s, 1H), 9.04 (s, 1H), 8.64(s, 1H), 7.84 (m, 1H), 7.68 (m, 1H), 4.33 (q, J=7.1, 4H), 1.34 (t=7.2,6H).

Mass spectrum (APCI): m/z=262 [M+H]⁺.

23.2: Ethyl6-[hydrazino(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate

To a solution of 625 mg of ethyl6-[ethoxy(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate in 12 mL ofethanol is added dropwise at 0-5° C. 0.2 mL of hydrazine hydrate. Thereaction mixture is stirred for 2 hours, a further 73 μL of hydrazinehydrate are added and the mixture is stirred for a further 2 hours whileallowing the temperature to rise to 25° C. The reaction mixture isconcentrated to dryness under reduced pressure and the residue is driedto give 600 mg of ethyl6-[hydrazino(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate, which isused without further purification in the rest of the synthesis.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.77 (broad s, 1H), 8.49 (s, 1H),7.70 (m, 1H), 7.53 (d, J=9.6, 1H), 5.67 (s, 2H), 5.15 (broad s, 2H),4.33 (q, J=7.1, 2H), 1.32 (t=7.1, 3H).

Mass spectrum (APCI): m/z=248 [M+H]⁺.

23.3: Ethyl6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate

A suspension of 580 mg of ethyl6-[hydrazino(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate in 6 mLof formic acid is heated for 20 hours at 85° C. The reaction mixture isconcentrated to less than 20% of its initial volume and diluted with 20mL of water. Solid sodium carbonate is added at 0-5° C. to obtain a pHof 8-9. The precipitate is filtered off by suction, and then purified bychromatography on silica, eluting with a mixture of dichloromethane andmethanol (98/2) to give 320 mg of ethyl6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate.

¹H NMR spectrum (DMSO-d6, δ in ppm): 14.5-14.0 (broad s, 1H), 9.25 (s,1H), 8.69 (s, 1H), 8.63 (broad s, 1H), 7.94 (dd, J=9.5, 1.5, 1H), 7.73(d, J=9.5, 1H), 4.33 (q, J=7.0, 2H), 1.33 (t=7.0, 3H)

Mass spectrum (APCI): m/z=258 [M+H]⁺.

23.4: 6-(1H-1,2,4-Triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

320 mg of ethyl6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate aresaponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3) to give 238 mg of6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid in theform of an off-white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 14.5-14.2 (broad s, 1H), 9.26 (s,1H), 8.66-8.62 (m, 2H), 7.91 (d, J=9.1, 1H), 7.73 (d, J=9.6, 1H).

Intermediate 246-(1H-1,2,3-Triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid 24.1:Ethyl 6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine-2-carboxylate

A mixture of 4 g of ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate,2.63 mL of ethynyltrimethylsilane and 888 mg ofdichlorobis(triphenylphosphine)palladium is degassed under vacuum. 240mg of degassed N,N-dimethylformamide and 3.52 mL of triethylamine areadded. The reaction mixture is degassed under argon, stirred at 50° C.for 50 hours and then cooled and diluted with 20 mL of water. Theprecipitate is filtered off by suction and washed with 5 mL of water andthen chromatographed on silica, eluting with mixtures of ethyl acetateand hexane (from 50/50 to 90/10). The fractions containing the expectedproduct are combined and concentrated to dryness under reduced pressureto give 3.6 g of ethyl6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine-2-carboxylate in theform of an off-white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.61 (s, 1H), 8.22 (s, 1H), 7.36(d, J=9.5, 1H), 7.07 (dd, J=9.5, 1.7, 1H), 4.07 (q, J=7.1, 2H), 1.08 (t,J=7.1, 3H), 0.01 (s, 9H).

Mass spectrum (APCI): m/z=287 [M+H]⁺.

24.2: Ethyl 6-ethynylimidazo[1,2-a]pyridine-2-carboxylate

To a solution of 500 mg of ethyl6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine-2-carboxylate in 10 mLof anhydrous tetrahydrofuran, cooled to 0° C. are added dropwise 1.58 mLof a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. Thereaction mixture is stirred for 30 minutes, 5 mL of water are then addedand the resulting mixture is extracted three times with 20 mL ofdichloromethane. The product is purified by chromatography on silica,eluting with mixtures of ethyl acetate and hexane (from 1/3 to 1/1). Thefractions containing the expected product are combined and concentratedto dryness under reduced pressure to give 280 mg of ethyl6-ethynylimidazo[1,2-a]pyridine-2-carboxylate in the form of a yellowsolid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.86 (d, J=1.0, 1H), 8.50 (d,J=0.6, 1H), 7.63 (d, J=9.4, 1H), 7.37 (d, J=1.7, 9.4, 1H), 4.32 (m, 3H),1.32 (t, J=7.1 Hz, 3H).

Mass spectrum (APCI): m/z=215 [M+H]⁺.

24.3: Ethyl6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate

To a solution of 220 mg of ethyl6-ethynylimidazo[1,2-a]pyridine-2-carboxylate and 0.21 mL ofazidotrimethylsilane in 4 mL of a mixture (9/1) of N,N-dimethylformamideand methanol are added 9.8 mg of cuprous iodide. The reaction mixture isstirred for 2 hours at 100° C. and then cooled, diluted with 4 mL ofdichloromethane, filtered through alumina and concentrated to dryness.The residue is chromatographed on silica, eluting with a mixture ofdichloromethane and ethanol (97/3). The fractions containing theexpected product are combined and concentrated to dryness under reducedpressure to give 125 mg of ethyl6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate in theform of an off-white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 15.5-15.0 (broad s, 1H), 9.14 (dd,J=1.1, 1.5, 1H), 8.60 (d, J=0.5, 1H), 8.40 (broad s, 1H), 7.82 (dd,J=1.7, 9.5, 1H), 7.75 (d, J=9.5, 1H), 4.33 (q, J=7.1, 2H), 1.33 (t,J=7.1, 3H).

Mass spectrum (APCI): m/z=258 [M+H]⁺.

24.4: 6-(1H-1,2,3-Triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

125 mg of ethyl6-(1H-1,2,3-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate aresaponified under conditions similar to those described for thepreparation of Intermediate 11 (step 11.3), to give 72 mg of6-(1H-1,2,3-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid in theform of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 16.0-15.0 (broad s, 1H), 9.23 (s,1H), 8.62 (s, 1H), 8.46 (broad s, 1H), 7.96 (dd, J=1.4, 9.5, 1H), 7.80(d, J=9.5, 1H).

Intermediate 25 Ethyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxylatehydrobromide (1:1)

To a solution of 4 g of2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in 40 mLof 1,2-dimethoxyethane are added 4.26 g of ethyl3-bromo-2-oxopropionate. The reaction mixture is stirred for 40 hours at20° C. The precipitate is filtered off by suction, washed with a smallamount of 1,2-dimethoxyethane and pentane and then taken up in 50 mL ofethanol and refluxed for 1 hour. The reaction mixture is concentrated todryness under reduced pressure. The oil obtained is redissolved in ethylether and the solution is concentrated under reduced pressure. The solidis filtered off by suction and washed with a small amount of ethyl etherto give 3.78 g of ethyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxylatehydrobromide (1:1) in the form of a white solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 1.27-1.38 (m, 15H), 4.36 (q, J=7.3Hz, 2H), 7.59 (d, J=9.3 Hz, 1H), 7.67 (d, J=9.3 Hz, 1H), 8.68 (s, 1H),8.97 (s, 1H).

Mass spectrum (EI): m/z 316 [M]⁺, 244 [M−CO₂Et+H]⁺.

Intermediate 26 2-Ethoxycarbonylimidazo[1,2-a]pyridine-6-boronic acid

To a solution of 2.5 g of2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in 50 mLof 1,2-dimethoxyethane are added 2.14 mL of ethyl3-bromo-2-oxopropionate. The reaction mixture is stirred for 3.5 hoursat 25° C., 50 mL of ethanol are then added and the resulting mixture isrefluxed for 16 hours. The reaction mixture is cooled and concentratedto dryness. The residue is suspended in 100 mL of water at 0° C. andtreated, while stirring vigorously, with solid sodium carbonate until apH of 8-9 is obtained. The precipitate is filtered off by suction andwashed with 100 mL of water at 0° C. and then dissolved in 150 mL ofmethanol. The solution is dried over magnesium sulfate, filtered,concentrated and dried under vacuum to give 2.36 g of2-ethoxycarbonylimidazo[1,2-a]pyridine-6-boronic acid in the form of acream-coloured solid.

¹H NMR spectrum (DMSO-d6, δ in ppm): 8.82 (d, J=0.9, 1H), 8.58 (s, 1H),8.35 (s, 2H) 7.61 (m, 2H), 4.33 (m, 2H), 1.32 (m, 3H)

Mass spectrum (APCI): m/z=235 [M+H]⁺.

The tables that follow illustrate the chemical structures (Table 1), thespectroscopic characteristics and the synthetic methods (Table 2) of afew examples of compounds according to the invention.

In this table:

-   -   the ratio in parentheses is the (acid/base) ratio, “HCl”        represents a compound in hydrochloride form, “TFA” represents a        compound in trifluoroacetate form and the ratio indicated in        parentheses is the (acid/base) ratio, the sign “-” means that        the compound is in base form;    -   “—CH₃” means methyl,

TABLE 1 (I)

Ex R₁ R₂ R₃ R₄ X salt Method 1 H

H H Ph — Ex 1 2 H

H H Ph — Ex 2 3 H

H H Ph — Ex 3 4 H

H H Ph — Ex 4 5 H

H H Ph HCl (1:1) Ex 5 6 H

H H Ph HCl (1:1) Ex 6 7 H

H H Ph HCl (1:1) Ex 7 8 H

H H Ph — Ex 8 9 H

H H Ph — Ex 9 10 H

H H Ph — Ex 10 11 H

H H Ph — Ex 11 12 H

H H Ph — Ex 12 13 H

H H Ph TFA (1:1) Ex 13 14 H

H H Ph — Ex 14 15 H

H H Ph — Ex 15 16 H

H H Ph — Ex 16 17 H

H H Ph HCl (1:1); HCl (1:2) Ex 17 18 H

H H Ph — Ex 18 19 —CH₃

H H Ph — Ex 19 20 H

H H Ph TFA (1:1) Ex 20 21 H

H H Ph — Ex 21 22 H

H H Ph — Ex 22 23 H

H H Ph — Ex 23 24 H

H H

— Ex 24 25 H

H H

— Ex 25 26 H

H H Ph — As per Ex 3 27 H

H H Ph HCl (1:1) As per Ex 5 28 H

H H Ph HCl (1:1) As per Ex 5 29 H

H H Ph — As per Ex 8 30 H

H H Ph TFA (1:1) As per Ex 9 31 H

H H Ph — As per Ex 7 32 H

H H Ph — As per Ex 3 33 H

H H

— As per Ex 3 34 H

H H Ph — As per Ex. 2 35 H

H H Ph — As per Ex 8 36 H

H H Ph — As per Ex 7 37 H

H H Ph — As per Ex 7 38 H

H H Ph — As per Ex 18 39 H

H H Ph — As per Interm. 20 and 1 40 H

H H Ph — As per Ex 8 41 H

H H Ph — As per Interm. 11 and 1 42 H

H H

— As per Ex 25 43 H

H H

— As per Ex 25 44 H

H H

— As per Ex 25 45 H

H H

— As per Ex 25 46 H

H H

— As per Ex 25 47 H

H H

— As per Ex 25 48 H

H H

— As per Ex 25 49 H

H H

— As per Ex 25 50 H

H H

— As per Ex 25 51 H

H H Ph — As per Ex 18 52 H

H H

— As per Ex 25 53 H

H H

— As per Ex 25 54 H

H H

— As per Ex 25 55 H

H H

— As per Ex 25 56 H

H H

— As per Ex 25 57 H

H H

— As per Ex 25 58 H

H H Ph — As per Ex 4 59 H

H H

— As per Ex 25 60 H

H H

— As per Ex 25 61 H

H H

— As per Ex 25 62 H

H H

— As per Ex 25 63 H

H H

— As per Ex 25 64 H

H H

— As per Ex 25 65 H

H H

— As per Ex 25 66 H

H H

— As per Ex 25 67 H

H H

— As per Ex 25 68 H

H H

— As per Ex 25 69 H

H H

— As per Ex 25 70 H

H H

— As per Ex 25 71 H

H H

— As per Ex 25 72 H

H H

— As per Ex 25 73 H

H H

— As per Ex 25 74 H

H H

— As per Ex 25 75 H

H H

— As per Ex 25 76 H

H H

— As per Ex 25 77 H

H H

— As per Ex 25 78 H

H H

— As per Ex 25 79 H

H H

— As per Ex 25 80 H

H H

HCl (1:2) As per Ex 25 81 H

H H

HCl (1:2) As per Ex 25 82 H

H H

HCl (1:2) As per Ex 25 83 H

H H

HCl (1:2) As per Ex 25 84 H

H H

HCl (1:2) As per Ex 25 85 H

H H

— As per Ex 25 86 H

H H

— As per Ex 25 87 H

H H

— As per Ex 25 88 H

H H

— As per Ex 25 89 H

H H

— As per Ex 25 90 H

H H

— As per Ex 25 91 H

H H

— As per Ex 25 92 H

H H

— As per Ex 25 93 H

H H

— As per Ex 25 94 H

H H

— As per Ex 25 95 H

H H

— As per Ex 25 96 H

H H

— As per Ex 25 97 H

H H

— As per Ex 25 98 H

H H

— As per Ex 25 99 H

H H

— As per Ex 25 100 H

H H

— As per Ex 25

TABLE 2 Ex Characterizations 1 ¹H NMR spectrum (DMSO-d6, δ in ppm): from3.97 to 4.14 (m, 4H), 5.87 (s, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.33 (t, J= 7.5 Hz, 2H), 7.41 (dd, J = 2.0 and 9.5 Hz, 1H), 7.69 (d, J = 9.5 Hz,1H), 7.90 (d, J = 7.5 Hz, 2H), 8.54 (s, 1H), 8.77 (broad s, 1H), 10.3(s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 310 [M + H]⁺. 2 ¹H NMRspectrum (DMSO-d6, δ in ppm): 7.10 (t, J = 8.0 Hz, 1H), 7.35 (broad t, J= 8.0 Hz, 2H), 7.56 (broad dd, J = 5.0 and 8.0 Hz, 1H), from 7.76 to7.83 (m, 2H), 7.91 (broad d, J = 8.0 Hz, 2H), 8.16 (td, J = 1.5 and 8.0Hz, 1H), 8.52 (s, 1H), 8.64 (dd, J = 1.5 and 5.0 Hz, 1H), 8.98 (m, 1H),9.09 (t, J = 1.5 Hz, 1H), 10.3 (s, 1H). Mass spectrum (LC-MS-DAD-ELSD):m/z 315 [M + H]⁺. 3 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.10 (t, J =7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.43 (dd, J = 5.0 and 8.0 Hz,1H), 7.78 (d, J = 9.5 Hz, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.97 (dt, J =2.0 and 8.0 Hz, 1H), 8.03 (d, J = 9.5 Hz, 1H), 8.12 (dd, J = 2.0 and 8.0Hz, 1H), 8.62 (s, 1H), 8.72 (broad d, J = 5.0 Hz, 1H), 9.43 (s, 1H),10.3 (s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 315 [M + H]⁺. 4 ¹H NMRspectrum (DMSO-d6, δ in ppm): 4.64 (d, J = 5.5 Hz, 2H), 5.41 (t, J = 5.5Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.79 (s,2H), 7.90 (d, J = 7.5 Hz, 2H), 8.08 (broad s, 1H), 8.53 (s, 1H), 8.59(broad s, 1H), 8.84 (broad s, 1H), 9.10 (broad s, 1H), 10.25 (s, 1H).Mass spectrum (LC-MS-DAD-ELSD): m/z 345 [M + H]⁺; m/z 389 [M + HCO₂]⁻. 5¹H NMR spectrum (DMSO-d6, δ in ppm): 4.68 (s, 2H), 7.12 (t, J = 8.0 Hz,2H), 7.38 (t, J = 8.0 Hz, 2H), 7.42 (broad d, J = 5.0 Hz, 1H), 7.82 (d,J = 9.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 2H), 8.00 (broad s, 1H), 8.21(broad d, J = 9.5 Hz, 1H), 8.67 (d, J = 5.0 Hz, 1H), 8.72 (s, 1H), 9.51(broad s, 1H), 10.45 (broad s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z345 [M + H]⁺. 6 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.89 (broad d, J =7.9 Hz, 1H), 7.11 (tt, J = 7.6, 1.2 Hz, 1H), 7.23 (dd, J = 7.9, 1.1 Hz,1H), 7.32-7.41 (m, 2H), 7.62 (very broad m, 3H), 7.84 (d, J = 9.6 Hz,1H), 7.81-7.97 (m, 4H), 8.67 (s, 1H), 9.29 (t, J = 1.1 Hz, 1H), 10.45(s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 330 [M + H]⁺. 7 ¹H NMRspectrum (DMSO-d6, δ in ppm): 7.10 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5Hz, 2H), 7.80 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 8.09 (broad s, 1H),8.62 (s, 1H), 8.84 (broad m, 1H), 9.09 (s, 1H), 10.3 (s, 1H). Massspectrum (LC-MS-DAD-ELSD): m/z 304 [M + H]⁺. 8 ¹H NMR spectrum (DMSO-d6,δ in ppm): 6.76 (d, J = 3.0 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.34 (t,J = 7.5 Hz, 2H), 7.71 (d, J = 9.5 Hz, 1H), from 7.81 to 7.92 (m, 4H),8.51 (s, 1H), 9.09 (s, 1H), 10.2 (s, 1H), 13.05 (broad m, 1H). Massspectrum (LC-MS-DAD-ELSD): m/z 304 [M + H]⁺, m/z 302 [M − H]⁻. 9 ¹H NMRspectrum (DMSO-d6, δ in ppm): 7.10 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5Hz, 2H), 7.78 (d, J = 9.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.99 (dd, J= 1.5 and 9.5 Hz, 1H), 8.61 (broad s, 1H), 8.68 (s, 1H), 9.30 (broad s,1H), 10.25 (s, 1H), 14.0 (very broad m, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 305 [M + H]⁺, m/z 303 [M − H]⁻. 10 ¹H NMR spectrum(DMSO-d6, δ in ppm): 6.48 (broad s, 1H), 6.89 (broad s, 1H), 7.10 (t, J= 7.5 Hz, 1H), 7.30 (broad s, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.60 (d, J= 9.5 Hz, 1H), 7.68 (dd, J = 1.5 and 9.5 Hz, 1H), 7.89 (d, J = 7.5 Hz,2H), 8.40 (s, 1H), 8.76 (broad s, 1H), 10.15 (broad s, 1H), 11.05 (broadm, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 303 [M + H]⁺, m/z 301 [M −H]⁻. 11 ¹H NMR spectrum (DMSO-d6, δ in ppm): 2.33 (s, 3H), 7.09 (t, J =7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.54 (broad s, 1H), 7.61 (d, J =9.5 Hz, 1H), 7.72 (dd, J = 1.5 and 9.5 Hz, 1H), 7.89 (d, J = 7.5 Hz,2H), 8.53 (s, 1H), 9.93 (broad s, 1H), 10.2 (s, 1H), 11.95 (broad m,1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 318 [M + H]⁺. 12 ¹H NMRspectrum (DMSO-d6, δ in ppm): 6.99 (broad s, 1H), 7.10 (t, J = 7.5 Hz,1H), 7.33 (t, J = 7.5 Hz, 2H), 7.69 (broad s, 2H), 7.82 (t, J = 1.5 Hz,1H), 7.90 (d, J = 7.5 Hz, 2H), 8.30 (broad s, 1H), 8.42 (s, 1H), 8.92(broad s, 1H), 10.25 (s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 304[M + H]⁺. 13 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.11 (t, J = 8.0 Hz,1H), 7.36 (t, J = 8.0 Hz, 2H), 7.65 (broad s, 1H), 7.79 (dd, J = 2.0 and9.5 Hz, 1H), 7.90 (m, 3H), 8.05 (broad s, 1H), 8.60 (s, 1H), 9.11 (broads, 1H), 9.20 (broad s, 1H), 10.3 (s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 304 [M + H]⁺. 14 ¹H NMR spectrum (DMSO-d6, δ inppm): 7.10 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.78 (m, 3H),7.90 (d, J = 7.5 Hz, 2H), 8.54 (s, 1H), 8.60 (s, 1H), 9.07 (broad s,1H), 10.25 (s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 305 [M + H]⁺. 15¹H NMR spectrum (DMSO-d6, δ in ppm): 7.10 (t, J = 7.5 Hz, 1H), 7.15 (m,3H), 7.33 (t, J = 7.5 Hz, 2H), 7.64 (d, J = 9.5 Hz, 1H), 7.81 (dd, J =1.5 and 9.5 Hz, 1H), 7.89 (d, J = 7.5 Hz, 2H), 8.61 (s, 1H), 8.92 (broads, 1H), 10.2 (s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 336 [M + H]⁺,m/z 334 [M − H]⁻. 16 ¹H NMR spectrum (DMSO-d6, δ in ppm): 1.64 (s, 3H),3.82 (m, 2H), 4.03 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5Hz, 2H), 7.39 (dd, J = 1.5 and 9.5 Hz, 1H), 7.64 (d, J = 9.5 Hz, 1H),7.90 (d, J = 7.5 Hz, 2H), 8.53 (s, 1H), 8.68 (broad s, 1H), 10.2 (broads, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 324 [M + H]⁺. 17 HCl (1:1)salt: ¹H NMR spectrum (DMSO-d6, δ in ppm): 4.04 (s, 4H), 7.12 (dt, J =7.3, 1.2 Hz, 1H), 7.31-7.40 (m, 2H), 7.82 (dd, J = 9.6, 1.9 Hz, 1H),7.87-7.95 (m, 3H), 8.76 (d, J = 0.8 Hz, 1H), 9.47 (dd, J = 1.9, 0.8 Hz,1H), 10.46 (s, 1H), 10.89 (broad s, 2H). Mass spectrum (LC-MS-DAD-ELSD):m/z 305 [M + H]⁺. 18 ¹H NMR spectrum (DMSO-d6, δ in ppm): 4.01 (s, 3H),6.85 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz,2H), 7.61 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 9.8 Hz, 1H), 7.85 (t, J =8.0 Hz, 1H), 7.91 (d, J = 7.7 Hz, 2H), 8.11 (broad d, J = 9.8 Hz, 1H),8.61 (s, 1H), 9.40 (broad s, 1H), 10.26 (s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 345 [M + H]⁺. 19 ¹H NMR spectrum (DMSO-d6, δ inppm): 2.74 (s, 3H), 7.10 (tt, dd, J = 7.6, 1.2 Hz, 1H), 7.36 (broad t, J= 7.6 Hz, 2H), 7.45 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.57 (d, J = 9.3Hz, 1H), 7.64-7.71 (m, 2H), 7.89-8.00 (m, 3H), 8.53 (d, J = 0.8 Hz, 1H),8.74 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 10.30 (s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 329 [M + H]⁺. 20 ¹H NMR spectrum (DMSO-d6, δ inppm): 7.10 (t, J = 7.7 Hz, 1H), 7.27-7.49 (m, 6H), 7.62 (dd, J = 9.6,2.2 Hz, 1H), 7.72 (d, J = 9.6 Hz, 1H), 7.84 (broad d, J = 7.7 Hz, 2H),8.49 (d, J = 0.8 Hz, 1H), 8.84 (broad s, 1H), 9.98 (broad s, 1H), 12.51(broad m, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 319 [M + H]⁺. 21 ¹HNMR spectrum (DMSO-d6, δ in ppm): 7.09 (tt, J = 7.8, 1.2 Hz, 1H), 7.29(broad s, 2H), 7.34 (broad t, J = 7.8 Hz, 2H), 7.49 (s, 1H), 7.63 (d, J= 9.5 Hz, 1H), 7.67 (dd, J = 9.5, 2.0 Hz, 1H), 7.89 (broad d, J = 7.8Hz, 2H), 8.45 (s, 1H), 8.62 (broad s, 1H), 10.19 (s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 336 [M + H]⁺, m/z 334 [M − H]⁻. 22 ¹H NMR spectrum(DMSO-d6, δ in ppm): 6.52 (broad d, J = 8.4 Hz, 1H), 6.99 (broad m, 1H),7.10 (broad t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 2H), 7.66 (broad t,J = 8.4 Hz, 1H), 7.74 (d, J = 9.4 Hz, 1H), 7.84 (broad d, J = 9.4 Hz,1H), 7.90 (d, J = 7.7 Hz, 2H), 8.58 (s, 1H), 9.16 (broad s, 1H), 10.29(s, 1H), 11.8 (very broad m, 1H). 23 ¹H NMR spectrum (DMSO-d6, δ inppm): 7.10 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.75 (d, J =9.5 Hz, 1H), 7.87 (dd, J = 9.5, 1.7 Hz, 1H), 7.90 (d, J = 7.8 Hz, 2H),8.42 (s, 1H), 8.57 (s, 1H), 9.20 (broad s, 1H), 10.26 (s, 1H), 15.3(very broad m, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 305 [M + H]⁺,m/z 303 [M − H]⁻. 24 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.93 (tt, J =9.5, 2.4 Hz, 1H), 6.98 (s, 1H), 7.70 (s, 2H), 7.74 (dd, J = 9.5, 2.4 Hz,2H), 7.82 (s, 1H), 8.29 (s, 1H), 8.47 (s, 1H), 8.93 (s, 1H), 10.74 (s,1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 340 [M + H]⁺. 25 ¹H NMRspectrum (DMSO-d6, δ in ppm): 6.92 (td, J = 8.3, 2.3, 1.0 Hz, 1H), 6.98(dd, J = 1.5, 0.9 Hz, 1H), 7.38 (td, J = 8.3, 6.8 Hz, 1H), 7.69 (d, J =1.4 Hz, 2H), 7.74 (ddd, J = 8.3, 2.3, 0.9 Hz, 1H), 7.82 (t, J = 1.5 Hz,1H), 7.88 (dt, J = 12.3, 2.3 Hz, 1H), 8.29 (dd, J = 1.5, 0.9 Hz, 1H),8.45 (s, 1H), 8.93 (t, J = 1.4 Hz, 1H), 10.50 (s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 322 [M + H]⁺. 26 ¹H NMR spectrum (DMSO-d6, δ inppm): 6.68 (dd, J = 2.0 and 3.5 Hz, 1H), 7.07 (d, J = 3.5 Hz, 1H), 7.10(t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.71 (d, J = 9.5 Hz, 1H),7.77 (dd, J = 2.0 and 9.5 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.90 (d, J= 7.5 Hz, 2H), 8.58 (s, 1H), 9.00 (broad s, 1H), 10.3 (s, 1H). Massspectrum (LC-MS-DAD-ELSD): m/z 304 [M + H]⁺. 27 ¹H NMR spectrum(DMSO-d6, δ in ppm): 4.69 (s, 2H), 7.11 (t, J = 8.0 Hz, 1H), 7.37 (t, J= 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.89(m, 3H), 7.98 (t, J = 8.0 Hz, 1H), 8.17 (broad d, 9.5 Hz, 1H), 8.67 (s,1H), 9.42 (broad s, 1H), 10.35 (broad s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 345 [M + H]⁺. 28 ¹H NMR spectrum (DMSO-d6, δ inppm): 7.11 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.59 (dd, J =6.0 and 8.0 Hz, 1H), 7.74 (broad d, J = 8.0 Hz, 1H), 7.80 (d, J = 9.5Hz, 1H), 7.85 (dd, J = 2.0 and 9.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H),8.30 (broad d, J = 6.0 Hz, 1H), 8.55 (s, 1H), 8.71 (t, J = 1.5 Hz, 1H),9.20 (broad s, 1H), 10.4 (broad s, 1H). Mass spectrum (LC-MS-DAD-ELSD):m/z 331 [M + H]⁺; m/z 329 [M − H]⁻. 29 ¹H NMR spectrum (DMSO-d6, δ inppm): 7.10 (t, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 2H), 7.69 (m, 2H),7.89 (d, J = 8.0 Hz, 2H), 8.11 (broad m, 2H), 8.40 (s, 1H), 8.90 (s,1H), 10.2 (s, 1H), 13.05 (broad m, 1H). Mass spectrum (LC-MS-DAD-ELSD):m/z 304 [M + H]⁺, m/z 302 [M − H]⁻. 30 ¹H NMR spectrum (DMSO-d6, δ inppm): 7.11 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.60 (s, 2H),from 7.83 to 7.95 (m, 4H), 8.70 (s, 1H), 9.23 (s, 1H), 10.3 (s, 1H)(broad signals). Mass spectrum (LC-MS-DAD-ELSD): m/z 304 [M + H]⁺, m/z302 [M − H]⁻. 31 ¹H NMR spectrum (DMSO-d6, δ in ppm): 3.71 (s, 3H), 7.10(t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.65 (d, J = 9.5 Hz, 1H),7.69 (s, 1H), 7.71 (s, 1H), 7.73 (dd, J = 1.5 and 9.5 Hz, 1H), 7.89 (d,J = 7.5 Hz, 2H), 8.55 (s, 1H), 8.97 (broad s, 1H), 10.2 (broad s, 1H).Mass spectrum (LC-MS-DAD-ELSD): m/z 318 [M + H]⁺. 32 ¹H NMR spectrum(DMSO-d6, δ in ppm): 7.10 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H),7.46 (s, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.90 (m, 3H), 8.31 (s, 1H), 8.67(s, 1H), 9.38 (broad s, 1H), 10.3 (s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 305 [M + H]⁺. 33 ¹H NMR spectrum (DMSO-d6, δ inppm): 6.94 (tt, J = 9.3, 2.4 Hz, 1H), 7.43 (ddd, J = 7.2, 4.8, 1.3 Hz,1H), 7.69-7.82 (m, 3H), 7.92-8.05 (m, 2H), 8.12 (dd, J = 9.6, 1.9 Hz,1H), 8.66 (d, J = 1.0 Hz, 1H), 8.71 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H),9.43 (dd, J = 1.9, 1.0 Hz, 1H), 10.79 (s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 351 [M + H]⁺. 34 ¹H NMR spectrum (DMSO-d6, δ inppm): 7.10 (t, J = 8.0 Hz, 1H), 7.35 (broad t, J = 8.0 Hz, 2H), from7.77 to 7.87 (m, 4H), 7.91 (broad d, J = 8.0 Hz, 2H), 8.54 (s, 1H), 8.71(m, 2H), 9.22 (broad s, 1H), 10.3 (s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 315 [M + H]⁺. 35 ¹H NMR spectrum (DMSO-d6, δ inppm): 7.10 (tt, J = 7.7, 1.2 Hz.1H), 7.13-7.26 (m, 2H), 7.35 (broad t, J= 7.7 Hz, 1H), 7.50 (broad d, J = 7.3 Hz, 1H), 7.71 (dt, J = 9.5, 0.9Hz, 1H), 7.79 (dd, J = 9.5, 2.2 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.91(broad d, J = 7.8 Hz, 2H), 8.00 (broad d, J = 7.8 Hz, 1H), 8.58 (d, J =0.8 Hz, 1H), 8.99 (broad s, 1H), 10.21 (s, 1H), 11.50 (broad s, 1H).Mass spectrum (LC-MS-DAD-ELSD): m/z 353 [M + H]⁺, m/z 351 [M − H]⁻. 36¹H NMR spectrum (DMSO-d6, δ in ppm): 7.10 (broad t, J = 7.7 Hz, 1H),7.20 (dd, J = 5.4, 3.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 2H), 7.59 (dd, J =3.7, 1.5 Hz, 1H), 7.63 (d, J = 5.4, 1.5 Hz, 1H), 7.66-7.78 (m, 2H), 7.90(m, 2H), 8.52 (s, 1H), 9.01 (broad s, 1H), 10.25 (s, 1H). 37 ¹H NMRspectrum (DMSO-d6, δ in ppm): 7.10 (broad t, J = 7.8 Hz, 1H), 7.35 (t, J= 7.8 Hz, 2H), 7.82 (d, J = 9.8 Hz, 1H), 7.91 (broad d, J = 7.8 Hz, 2H),8.14 (dd, J = 9.8, 1.9 Hz, 1H), 8.63 (broad s, 1H), 8.68 (broad d, J =2.7 Hz, 1H), 8.77 (dd, J = 2.7, 1.5 Hz.1H), 9.32 (broad d, J = 1.5 Hz,1H), 9.51 (dd, J = 1.9, 1.0 Hz, 1H), 10.31 (s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 316 [M + H]⁺. 38 ¹H NMR spectrum (DMSO-d6, δ inppm): 7.10 (tt, J = 7.7, 1.2 Hz, 1H), 7.35 (broad t, J = 7.7 Hz, 2H),7.43-7.53 (m, 2H), 7.71 (dd, J = 9.6, 0.9 Hz, 1H), 7.79-7.86 (m, 2H),7.91 (broad d, J = 7.7 Hz, 2H), 8.42 (m, 1H), 8.61 (d, J = 0.8 Hz, 1H),9.36 (broad s, 1H), 10.28 (s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z331 [M + H]⁺. 39 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.10 (broad t, J =7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 2H), 7.82 (broad d, J = 9.8 Hz, 1H),7.86 (dd, J = 9.8, 1.5 Hz, 1H), 7.91 (d, J = 7.7 Hz, 2H), 8.52 (s, 1H),9.18 (broad s, 1H), 9.22 (s, 2H), 9.25 (s, 1H), 10.30 (s, 1H). Massspectrum (LC-MS-DAD-ELSD): m/z 316 [M + H]⁺. 40 ¹H NMR spectrum(DMSO-d6, δ in ppm): 7.10 (broad t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8Hz, 2H), 7.59 (dd, J = 5.1, 1.5 Hz, 1H), 7.71 (d, J = 9.8 Hz, 1H), 7.74(dd, J = 5.1, 2.9 Hz, 1H), 7.81 (dd, J = 9.8, 2.0 Hz, 1H), 7.90 (m, 2H),7.99 (dd, J = 2.9, 1.5 Hz, 1H), 8.46 (s, 1H), 9.05 (broad s, 1H), 10.24(s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 320 [M + H]⁺. 41 ¹H NMRspectrum (DMSO-d6, δ in ppm): 5.99 (dd, J = 7.0, 3.6 Hz, 1H), 7.06 (t, J= 3.6 Hz, 1H), 7.09 (tt, J = 7.7, 1.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 2H),7.67-7.76 (m, 2H), 7.89 (m, 2H), 8.53 (s, 1H), 8.91 (s, 1H), 10.22 (s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 322 [M + H]⁺. 42 ¹H NMR spectrum(DMSO-d6, δ in ppm): 6.92 (m, 1H), 7.33-7.45 (m, 2H), 7.76 (m, 2H), 7.89(dt, J = 11.6, 2.4 Hz, 1H), 7.96 (td, J = 7.8, 1.6 Hz, 1H), 8.03 (dt, J= 7.8, 1.6 Hz, 1H), 8.12 (dd, J = 9.6, 1.9 Hz, 1H), 8.64 (d, J = 0.8 Hz,1H), 8.71 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 9.43 (dd, J = 1.9, 0.8 Hz,1H), 10.55 (s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 333 [M + H]⁺. 43¹H NMR spectrum (DMSO-d6, δ in ppm): 7.16-7.38 (m, 3H), 7.43 (ddd, J =7.5, 4.7, 1.3 Hz, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.96 (td, J = 7.5, 1.3Hz, 1H), 8.03 (broad d, J = 7.5 Hz, 1H), 8.06-8.15 (m, 2H), 8.65 (s,1H), 8.71 (broad d, J = 4.7 Hz, 1H), 9.43 (broad s, 1H), 9.85 (broad s,1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 333 [M + H]⁺. 44 ¹H NMRspectrum (DMSO-d6, δ in ppm): 7.06 (m, 1H), 7.45-7.47 (m, 2H), 7.82(broad d, J = 9.8 Hz, 1H), 7.91-8.06 (m, 3H), 8.14 (dd, J = 9.8, 1.7 Hz,1H), 8.69 (d, J = 0.9 Hz, 1H), 8.71 (broad d, J = 5.4 Hz, 1H), 9.43(broad s, 1H), 9.89 (broad s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z351 [M + H]⁺. 45 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.17-7.33 (m, 2H),7.43 (ddd, J = 7.9, 4.8, 1.0 Hz, 1H), 7.77 (partially masked m, 1H),7.80 (dt, J = 9.6, 0.9 Hz, 1H), 7.96 (dt, J = 7.9, 1.8 Hz, 1H), 8.03(dt, J = 7.9, 1.0 Hz, 1H), 8.13 (dd, J = 9.6, 1.8 Hz, 1H), 8.66 (d, J =0.9 Hz, 1H), 8.71 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 9.43 (dd, J = 1.8,0.9 Hz, 1H), 10.09 (broad s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z351 [M + H]⁺. 46 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.07 (broad s,2H), 6.49 (dd, J = 8.3, 0.9 Hz, 1H), 6.92 (broad td, J = 8.3, 2.5 Hz,1H), 7.09 (dd, J = 7.4, 0.9 Hz, 1H), 7.38 (td, J = 8.3, 6.9 Hz, 1H),7.52 (dd, J = 8.3, 7.4 Hz, 1H), 7.70 (dt, J = 9.6, 0.9 Hz, 1H), 7.75(broad dd, J = 8.3, 1.8 Hz, 1H), 7.88 (dt, J = 11.7, 2.5 Hz, 1H), 7.99(dd, J = 9.7, 1.8 Hz, 1H), 8.62 (d, J = 0.9 Hz, 1H), 9.19 (dd, J = 1.8,0.9 Hz, 1H), 10.52 (broad s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z348 [M + H]⁺. 47 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.47 (td, J = 2.8,1.7 Hz, 1H), 6.84-6.95 (m, 2H), 7.31 (dt, J = 2.8, 1.7 Hz, 1H), 7.37(td, J = 8.3, 6.8 Hz, 1H), 7.60 (dt, J = 9.4, 0.9 Hz, 1H), 7.67 (dd, J =9.4, 1.6 Hz, 1H), 7.74 (broad d, J = 8.3 Hz, 1H), 7.88 (dt, J = 12.1,2.6 Hz, 1H), 8.42 (d, J = 0.9 Hz, 1H), 8.76 (broad s, 1H), 10.45 (broads, 1H), 11.06 (broad m, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 321[M + H]⁺. 48 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.77 (broad s, 1H),6.92 (td, J = 8.5, 2.6 Hz, 1H), 7.38 (td, J = 8.3, 6.8 Hz, 1H),7.67-7.78 (m, 2H), 7.84-7.92 (m, 3H), 8.55 (s, 1H), 9.09 (broad s, 1H),10.51 (broad s, 1H), 13.05 (broad s, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 322 [M + H]⁺, m/z 320 [M − H]⁻. 49 ¹H NMR spectrum(DMSO-d6, δ in ppm): 6.66 (dd, J = 3.4, 1.9 Hz, 1H), 6.85-6.97 (tdd, J =8.5, 2.5, 1.0 Hz, 1H), 7.05 (dd, J = 3.4, 0.8 Hz, 1H), 7.38 (td, J =8.3, 6.8 Hz, 1H), 7.66-7.79 (m, 3H), 7.83 (dd, J = 1.9, 0.8 Hz, 1H),7.87 (d, J = 11.9, 2.5 Hz, 1H), 8.58 (d, J = 0.6 Hz, 1H), 8.99 (t, J =1.5 Hz, 1H), 10.51 (broad s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z322 [M + H]⁺. 50 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.92 (tdd, J =8.5, 2.6, 1.0 Hz, 1H), 7.38 (td, J = 8.5, 6.8 Hz, 1H), 7.45 (d, J = 0.9Hz, 1H), 7.76 (ddd, J = 8.5, 2.6, 1.0 Hz, 1H), 7.81 (dt, J = 9.5, 1.0Hz, 1H), 7.88 (dt, J = 12.0, 2.6Hz.1H), 7.92 (dd, J = 9.5, 1.9 Hz, 1H),8.31 (d, J = 0.9 Hz, 1H), 8.69 (d, J = 1.0 Hz, 1H), 9.38 (dd, J = 1.9,1.0 Hz, 1H), 10.58 (broad s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z323 [M + H]⁺. 51 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.10 (tt, J = 7.5,1.3 Hz, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.52 (t, J = 4.9 Hz, 1H), 7.79(d, J = 9.8 Hz, 1H), 7.91 (m, 2H), 8.30 (dd, J = 9.8, 1.7 Hz, 1H), 8.74(s, 1H), 8.96 (d, J = 4.9 Hz, 2H), 9.69 (broad s, 1H), 10.31 (s, 1H).Mass spectrum (LC-MS-DAD-ELSD): m/z 316 [M + H]⁺. 52 ¹H NMR spectrum(DMSO-d6, δ in ppm): 6.91 (tdd, J = 8.3, 2.2, 1.0 Hz, 1H), 7.37 (td, J =8.3, 6.8 Hz, 1H), 7.65 (dt, J = 9.5, 0.9 Hz, 1H), 7.69-7.79 (m, 3H),7.81 (dd, J = 9.5, 1.7 Hz, 1H), 7.87 (dt, J = 11.7, 2.2 Hz, 1H), 8.58(d, J = 0.9 Hz, 1H), 9.00 (dd, J = 1.7, 0.9 Hz, 1H), 10.46 (s, 1H),12.28 (broad m, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 322 [M + H]⁺,m/z 320 [M − H]⁻. 53 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.92 (tdd, J =8.4, 2.6, 1.1 Hz, 1H), 7.38 (td, J = 8.4, 6.9 Hz, 1H), 7.72-7.81 (m,2H), 7.88 (ddt, J = 12.1, 2.2 Hz, 1H), 7.99 (broad d, J = 9.6 Hz, 1H),8.69 (s, 1H), 8.71 (broad s, 1H), 9.32 (broad s, 1H), 10.54 (broad s,1H), 14.26 (broad m, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 323 [M +H]⁺. 54 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.91 (tdd, J = 8.5, 2.6,1.0 Hz, 1H), 7.38 (td, J = 8.5, 6.8 Hz, 1H), 7.67-7.82 (m, 4H), 7.86(dt, J = 12.0, 2.2 Hz, 1H), 8.55 (s, 1H), 8.86 (broad s, 1H), 8.90(broad m, 2H), 10.61 (s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 354[M + H]⁺, m/z 352 [M − H]⁻. 55 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.92(tdd, J = 8.5, 2.6, 1.0 Hz, 1H), 7.38 (td, J = 8.3, 6.8 Hz, 1H),7.73-7.79 (m, 2H), 7.84-7.92 (m, 2H), 8.44 (broad m, 1H), 8.60 (broad s,1H), 9.20 (broad s, 1H), 10.53 (broad s, 1H), 15.24 (broad m, 1H). Massspectrum (LC-MS-DAD-ELSD): m/z 323 [M + H]⁺. 56 ¹H NMR spectrum(DMSO-d6, δ in ppm): 6.86-6.98 (tdd, J = 8.4, 2.7, 0.8 Hz, 1H), 7.37(td, J = 8.4, 6.8 Hz, 1H), 7.63-7.78 (m, 3H), 7.88 (dt, J = 11.8, 2.3Hz, 1H), 7.99 (broad m, 1H), 8.24 (broad m, 1H), 8.44 (s, 1H), 8.90 (t,J = 1.4 Hz, 1H), 10.48 (broad s, 1H), 13.07 (broad m, 1H). Mass spectrum(LC-MS-DAD-ELSD): m/z 322 [M + H]⁺, m/z 320 [M − H]⁻. 57 ¹H NMR spectrum(DMSO-d6, δ in ppm): 4.49 (d, J = 5.5 Hz, 2H), 5.30 (t, J = 5.5 Hz, 1H),6.47 (d, J = 3.4 Hz, 1H), 6.91 (tdd, J = 8.4, 2.3, 0.9 Hz, 1H), 6.98 (d,J = 3.4 Hz, 1H), 7.37 (td, J = 8.4, 6.8 Hz, 1H), 7.67-7.77 (m, 3H), 7.87(ddd, J = 12.1, 2.3 Hz, 1H), 8.60 (s, 1H), 8.95 (t, J = 1.4 Hz, 1H),10.50 (s, 1H). Mass spectrum (LC-MS-DAD-ELSD): m/z 352 [M + H]⁺, m/z 350[M − H]⁻. 58 ¹H NMR spectrum (DMSO-d6, δ in ppm): 4.53 (d, J = 5.6 Hz,2H), 5.37-5.47 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz,2H), 7.59-7.67 (m, 2H), 7.78 (dd, J = 9.5, 1.5 Hz, 1H), 7.89 (d, J = 7.6Hz, 2H), 8.54 (s, 1H), 8.96 (s, 1H), 10.16 (broad s, 1H), 12.15 (broadm, 1H). Mass spectrum (LC-MS-ES+/−): m/z 332 [M + H]⁻, m/z 334 [M + H]⁺59 ¹H NMR spectrum (DMSO-d6, δ in ppm): 2.58 (s, 3H), 6.90-6.97 (m, 1H),7.29 (d, J = 6.8 Hz, 1H), 7.75 (d, J = 9.5 Hz, 3H) 7.79-7.87 (m, 2H)8.10 (dd, J = 9.5, 1.7 Hz, 1H), 8.67 (s, 1H), 9.37 (broad s, 1H), 10.77(broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z 363 [M + H]⁻, m/z 365[M + H]⁺ 60 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.21 (td, J = 7.9, 1.6Hz, 1H), 7.38-7.47 (m, 2H), 7.59 (dd, J = 7.9, 1.6 Hz, 1H), 7.82 (d, J =9.6 Hz, 1H), 7.92-8.07 (m, 2H), 8.14 (dd, J = 9.6, 1.8 Hz, 1H), 8.36(dd, J = 8.3, 1.6 Hz, 1H), 8.67-8.74 (m, 2H), 9.43 (broad s, 1H), 9.96(broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z 349 [M + H]⁺ 61 ¹H NMRspectrum (DMSO-d6, δ in ppm): 6.47 (m, 1H), 6.88 (m, 1H), 6.91 (tt, J =9.2, 2.4 Hz, 1H), 7.31 (m, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.68 (dd, J =9.5, 1.8 Hz, 1H), 7.74 (m, 2H), 8.44 (s, 1H), 8.76 (broad s, 1H), 10.69(broad s, 1H), 11.06 (broad m, 1H). Mass spectrum (LC-MS-ES+/−): m/z 337[M + H]⁻, m/z 339 [M + H]⁺ 62 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.47(m, 1H), 6.87 (m, 1H), 7.13-7.38 (m, 4H), 7.64 (d, J = 9.5 Hz, 1H), 7.70(dd, J = 9.5, 1.7 Hz, 1H), 8.13 (td, J = 7.8, 2.0 Hz, 1H), 8.43 (s, 1H),8.76 (broad s, 1H), 9.76 (broad s, 1H), 11.05 (broad m, 1H). Massspectrum (LC-MS-ES+/−): m/z 319 [M + H]⁻, m/z 321 [M + H]⁺ 63 ¹H NMRspectrum (DMSO-d6, δ in ppm): 6.47 (m, 1H), 6.87 (m, 1H), 7.03 (m, 1H),7.32 (m, 1H), 7.40 (ddd, J = 10.4, 9.1, 5.0 Hz, 1H), 7.65 (d, J = 9.5Hz, 1H), 7.71 (dd, J = 9.5, 1.7 Hz, 1H), 8.04 (ddd, J = 10.4, 6.2, 3.3Hz, 1H), 8.46 (s, 1H), 8.76 (broad s, 1H), 9.81 (broad s, 1H), 11.07(broad m, 1H). Mass spectrum (LC-MS-ES+/−): m/z 337 [M + H]⁻, m/z 339[M + H]⁺ 64 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.47 (m, 1H), 6.87 (m,1H), 7.17-7.29 (m, 2H), 7.32 (m, 1H), 7.64 (d, J = 9.5 Hz, 1H), 7.70(dd, J = 9.5, 1.7 Hz, 1H), 7.83 (m, 1H), 8.44 (s, 1H), 8.76 (broad s,1H), 9.98 (broad s, 1H), 11.05 (broad m, 1H). Mass spectrum(LC-MS-ES+/−): m/z 337 [M + H]⁻, m/z 339 [M + H]⁺ 65 ¹H NMR spectrum(DMSO-d6, δ in ppm): 6.76 (d, J = 2.2 Hz, 1H), 6.93 (tt, J = 9.4, 2.4Hz, 1H), 7.67-7.94 (m, 5H), 8.56 (s, 1H), 9.09 (broad s, 1H), 10.74(broad s, 1H), 13.05 (broad m, 1H). Mass spectrum (LC-MS-ES+/−): m/z 338[M + H]⁻, m/z 340 [M + H]⁺ 66 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.66(dd, J = 3.4, 1.9 Hz, 1H), 7.06 (d, J = 3.4 Hz, 1H), 7.16-7.39 (m, 3H),7.77 (m, 2H), 7.83 (d, J = 1.9 Hz, 1H), 8.04-8.14 (m, 1H), 8.59 (s, 1H),8.98 (broad s, 1H), 9.80 (broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z322 [M + H]⁺ 67 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.66 (dd, J = 3.4,1.9 Hz, 1H), 6.97-7.13 (m, 2H), 7.40 (ddd, J = 10.5, 9.1, 5.0 Hz, 1H),7.72-7.82 (m, 2H), 7.83 (dd, J = 1.9, 0.9 Hz, 1H), 8.01 (ddd, J = 10.3,6.2, 3.2 Hz, 1H), 8.62 (s, 1H), 8.98 (broad s, 1H), 9.84 (broad s, 1H).Mass spectrum (LC-MS-ES+/−): m/z 340 [M + H]⁺ 68 ¹H NMR spectrum(DMSO-d6, δ in ppm): 6.66 (dd, J = 3.4, 1.9 Hz, 1H), 7.06 (d, J = 3.4Hz, 1H), 7.17-7.34 (m, 2H), 7.70-7.87 (m, 4H), 8.61 (s, 1H), 8.99 (broads, 1H), 10.04 (broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z 340 [M +H]⁺ 69 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.66 (dd, J = 3.4, 1.8 Hz,1H), 7.07 (d, J = 3.4 Hz, 1H), 7.20 (m, 1H), 7.37-7.47 (m, 1H), 7.58(dd, J = 8.2, 1.6 Hz, 1H), 7.78 (m, 2H), 7.81-7.86 (m, 1H), 8.36 (dd, J= 8.2, 1.6 Hz, 1H), 8.62 (s, 1H), 8.96-9.03 (broad s, 1H), 9.92 (broads, 1H). Mass spectrum (LC-MS-ES+/−): m/z 338 [M + H]⁺ 70 ¹H NMR spectrum(DMSO-d6, δ in ppm): 7.06 (m, 1H), 7.40 (ddd, J = 10.4, 9.1, 5.1 Hz,1H), 7.46 (d, J = 0.9 Hz, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.85 (dd, J =9.6, 1.7 Hz, 1H), 7.97 (m, 1H), 8.31 (d, J = 0.9 Hz, 1H), 8.72 (s, 1H),9.37 (broad s, 1H), 9.91 (broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z341 [M + H]⁺ 71 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.17-7.25 (m, 1H),7.38-7.47 (m, 2H), 7.58 (dd, J = 8.0, 1.4 Hz, 1H), 7.85 (d, J = 9.5 Hz,1H), 7.92 (dd, J = 9.5, 1.7 Hz, 1H), 8.29-8.34 (m, 2H), 8.72 (s, 1H),9.38 (broad s, 1H), 9.95 (broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z339 [M + H]⁺ 72 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.95-7.00 (m, 1H),7.14-7.39 (m, 3H), 7.68-7.78 (m, 2H), 7.80-7.84 (m, 1H), 8.06-8.15 (m,1H), 8.30 (broad s, 1H), 8.46 (s, 1H), 8.92 (broad s, 1H), 9.80 (broads, 1H). Mass spectrum (LC-MS-ES+/−): m/z 322 [M + H]⁺ 73 ¹H NMR spectrum(DMSO-d6, δ in ppm): 6.96-7.11 (m, 2H), 7.33-7.46 (m, 1H), 7.69-7.79 (m,2H), 7.79-7.85 (m, 1H), 7.98-8.07 (m, 1H), 8.29 (broad s, 1H), 8.49 (s,1H), 8.92 (broad s, 1H), 9.85 (broad s, 1H). Mass spectrum(LC-MS-ES+/−): m/z 340 [M + H]⁺ 74 ¹H NMR spectrum (DMSO-d6, δ in ppm):6.93-7.00 (m, 1H), 7.20-7.29 (m, 2H), 7.67-7.86 (m, 4H), 8.29 (broad s,1H), 8.47 (s, 1H), 8.92 (broad s, 1H), 10.04 (broad s, 1H). Massspectrum (LC-MS-ES+/−): m/z 340 [M + H]⁺ 75 ¹H NMR spectrum (DMSO-d6, δin ppm): 6.98 (dd, J = 1.9, 0.9 Hz, 1H), 7.20 (td, J = 7.9, 1.6 Hz, 1H),7.42 (td, J = 7.9 1.6 Hz, 1H), 7.58 (dd, J = 7.9, 1.6 Hz, 1H), 7.72 (dd,J = 9.5, 1.7 Hz, 1H), 7.76 (d, J = 9.5 Hz, 1H), 7.82 (t, J = 1.9 Hz,1H), 8.30 (broad s, 1H), 8.37 (dd, J = 7.9, 1.6 Hz, 1H), 8.49 (s, 1H),8.93 (broad s, 1H), 9.93 (broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z338 [M + H]⁺ 76 ¹H NMR spectrum (DMSO-d6, δ in ppm): 4.49 (d, J = 5.3Hz, 2H), 5.30 (t, J = 5.3 Hz, 1H), 6.47 (d, J = 3.4 Hz, 1H), 6.99 (d, J= 3.4 Hz, 1H), 7.21-7.28 (m, 2H), 7.73-7.83 (m, 3H), 8.62 (s, 1H), 8.94(broad s, 1H), 10.03 (broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z 368[M + H]⁻, m/z 370 [M + H]⁺ 77 ¹H NMR spectrum (DMSO-d6, δ in ppm):7.14-7.40 (m, 3H), 7.82 (d, J = 9.5 Hz, 1H), 7.97 (dd, J = 9.5, 1.7 Hz,1H), 8.03-8.15 (m, 1H), 8.63 (broad m, 1H), 8.71 (s, 1H), 9.31 (broad s,1H), 9.84 (broad s, 1H), 14.19-14.39 (broad m, 1H). Mass spectrum(LC-MS-ES+/−): m/z 321 [M + H]⁻, m/z 323 [M + H]⁺ 78 ¹H NMR spectrum(DMSO-d6, δ in ppm): 7.17-7.24 (m, 1H), 7.38-7.45 (m, 1H), 7.58 (dd, J =8.0.1.4 Hz, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.99 (dd, J = 9.5, 1.7 Hz,1H), 8.35 (dd, J = 8.2, 1.4 Hz, 1H), 8.61-8.67 (broad m, 1H), 8.73 (s,1H), 9.33 (broad s, 1H), 9.95 (broad s, 1H), 14.14-14.42 (broad m, 1H).Mass spectrum (LC-MS-ES+/−): m/z 337 [M + H]⁻, m/z 339 [M + H]⁺ 79 ¹HNMR spectrum (DMSO-d6, δ in ppm): 7.36-7.46 (m, 2H), 7.72-7.83 (m, 2H),7.87 (dd, J = 7.8, 1.2 Hz, 1H), 7.94-8.06 (m, 3H), 8.14 (dd, J = 9.8,1.7 Hz, 1H), 8.64-8.78 (m, 2H), 9.43 (s, 1H), 10.46 (broad s, 1H). Massspectrum (LC-MS-ES+/−): m/z 340 [M + H]⁺ 80 ¹H NMR spectrum (DMSO-d6, δin ppm): 6.89-7.03 (m, 2H), 7.25 (d, J = 7.4 Hz, 1H), 7.65-8.04 (m, 7H),8.69 (s, 1H), 9.33 (s, 1H), 10.90 (broad s, 1H). Mass spectrum(LC-MS-ES+/−): m/z 366 [M + H]⁺ 81 ¹H NMR spectrum (DMSO-d6, δ in ppm):6.88 (d, J = 8.7 Hz, 1H), 7.16-7.40 (m, 4H), 7.6 (broad m, 2H),7.82-7.98 (m, 3H), 8.00-8.10 (m, 1H), 8.67 (s, 1H), 9.27 (s, 1H), 9.94(broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z 348 [M + H]⁺ 82 ¹H NMRspectrum (DMSO-d6, δ in ppm): 6.89 (d, J = 8.7 Hz, 1H), 7.02-7.12 (m,1H), 7.22 (d, J = 7.4 Hz, 1H), 7.41 (ddd, J = 10.3, 9.2, 5.0 Hz, 1H),7.6 (m, 2H), 7.84-8.02 (m, 4H), 8.69 (s, 1H), 9.27 (s, 1H), 9.96 (broads, 1H). Mass spectrum (LC-MS-ES+/−): m/z 366 [M + H]⁺ 83 ¹H NMR spectrum(DMSO-d6, δ in ppm): 6.98 (d, J = 8.4 Hz, 1H), 7.20-7.35 (m, 3H),7.69-7.78 (m, 1H), 7.87-8.01 (m, 3H), 7.95 (broad m, 2H), 8.69 (s, 1H),9.31 (s, 1H), 10.23 (broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z 366[M + H]⁺ 84 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.89 (d, J = 8.7 Hz,1H), 7.17-7.27 (m, 2H), 7.38-7.48 (m, 1H), 7.59 (dd, J = 7.9, 1.4 Hz,1H), 7.60 (m, 2H), 7.83-7.98 (m, 3H), 8.32 (dd, J = 8.2, 1.4 Hz, 1H),8.68 (s, 1H), 9.28 (s, 1H), 10.01 (broad s, 1H). Mass spectrum(LC-MS-ES+/−): m/z 364 [M + H]⁺ 85 ¹H NMR spectrum (DMSO-d6, δ in ppm):6.47 (m, 1H), 6.87 (m, 1H), 7.19 (td, J = 7.9, 1.6 Hz, 1H), 7.32 (m,1H), 7.41 (td, J = 7.9, 1.6 Hz, 1H), 7.58 (dd, J = 7.9, 1.6 Hz, 1H),7.65 (d, J = 9.5 Hz, 1H), 7.71 (dd, J = 9.5, 1.6 Hz, 1H), 8.39 (dd, J =7.9, 1.6 Hz, 1H), 8.46 (s, 1H), 8.76 (broad s, 1H), 9.91 (broad s, 1H),11.05 (broad m, 1H). Mass spectrum (LC-MS-ES+/−): m/z 335 [M + H]⁻, m/z337 [M + H]⁺ 86 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.77 (d, J = 2.3Hz, 1H), 7.15-7.41 (m, 3H), 7.70-7.95 (m, 3H), 8.10 (m, 1H), 8.56 (s,1H), 9.08 (broad s, 1H), 9.81 (broad s, 1H), 13.04 (broad m, 1H). Massspectrum (LC-MS-ES+/−): m/z 320 [M + H]⁻, m/z 322 [M + H]⁺ 87 ¹H NMRspectrum (DMSO-d6, δ in ppm): 6.78 (broad s, 1H), 7.20 (td, J = 8.0, 1.4Hz, 1H), 7.36-7.47 (m, 1H), 7.58 (dd, J = 8.0, 1.4 Hz, 1H), 7.75 (d, J =9.5 Hz, 1H), 7.86 (broad s, 1H), 7.91 (broad d, J = 9.5 Hz, 1H), 8.37(dd, J = 8.0, 1.4 Hz, 1H), 8.59 (s, 1H), 9.09 (broad s, 1H), 9.94 (s,1H), 13.06 (broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z 336 [M + H]⁻,m/z 338 [M + H]⁺ 88 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.66 (dd, J =3.4, 1.7 Hz, 1H), 6.93 (tt, J = 9.4, 2.4 Hz, 1H), 7.05 (d, J = 3.4 Hz,1H), 7.67-7.80 (m, 4H) 7.83 (m, 1H), 8.60 (s, 1H), 8.99 (broad s, 1H),10.74 (broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z 338 [M + H]⁻, m/z340 [M + H]⁺ 89 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.94 (tt, J = 9.5,2.2 Hz, 1H), 7.46 (d, J = 0.9 Hz, 1H), 7.75 (m, 2H), 7.81 (d, J = 9.6Hz, 1H), 7.92 (dd, J = 9.6, 1.9 Hz, 1H), 8.31 (d, J = 0.9 Hz, 1H), 8.71(broad s, 1H), 9.38 (broad s, 1H), 10.81 (broad s, 1H). Mass spectrum(LC-MS-ES+/−): m/z 339 [M + H]⁻, m/z 341 [M + H]⁺ 90 ¹H NMR spectrum(DMSO-d6, δ in ppm): 7.16-7.39 (m, 3H), 7.46 (d, J = 0.8 Hz, 1H), 7.84(d, J = 9.5 Hz, 1H), 7.92 (dd, J = 9.6, 1.9 Hz, 1H), 8.05 (m, 1H), 8.31(d, J = 0.8 Hz, 1H), 8.69 (s, 1H), 9.37 (broad s, 1H), 9.87 (broad s,1H). Mass spectrum (LC-MS-ES+/−): m/z 323 [M + H]⁺ 91 ¹H NMR spectrum(DMSO-d6, δ in ppm): 7.18-7.33 (m, 2H), 7.46 (s, 1H), 7.74 (m, 1H), 7.84(d, J = 9.5 Hz, 1H), 7.92 (d, J = 9.5 Hz, 1H), 8.31 (s, 1H), 8.70 (s,1H), 9.37 (s, 1H), 10.12 (s, 1H), (broad signals) Mass spectrum(LC-MS-ES+/−): m/z 339 [M + H]⁻, m/z 341 [M + H]⁺ 92 ¹H NMR spectrum(DMSO-d6, δ in ppm): 4.49 (d, J = 5.6 Hz, 2H), 5.30 (t, J = 5.6 Hz, 1H),6.46 (d, J = 3.4 Hz, 1H), 6.92 (tt, J = 9.3, 2.4 Hz, 1H), 6.98 (d, J =3.4 Hz, 1H), 7.65-7.83 (m, 4H), 8.64 (s, 1H), 8.98 (broad s, 1H), 10.74(broad s, 1H). Mass spectrum (LC-MS-ES+/−): m/z 368 [M + H]⁻, m/z 370[M + H]⁺ 93 ¹H NMR spectrum (DMSO-d6, δ in ppm): 4.48 (d, J = 5.3 Hz,2H), 5.30 (t, J = 5.3 Hz, 1H), 6.47 (d, J = 3.3 Hz, 1H), 6.96-7.11 (m,1H), 6.99 (d, J = 3.3 Hz, 1H), 7.35-7.46 (m, 1H), 7.76 (m, 2H),7.96-8.05 (m, 1H), 8.64 (s, 1H), 8.95 (broad s, 1H), 9.85 (broad s, 1H).Mass spectrum (LC-MS-ES+/−): m/z 368 [M + H]⁻, m/z 370 [M + H]⁺ 94 ¹HNMR spectrum (DMSO-d6, δ in ppm): 7.19-7.28 (m, 2H), 7.65-7.72 (m, 2H),7.75-7.86 (m, 3H), 8.59 (s, 1H), 8.99 (broad s, 1H), 10.27-11.48 (broadm, 1H). Mass spectrum (LC-MS-ES+/−): m/z 338 [M + H]⁻, m/z 340 [M + H]⁺95 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.05 (m, 1H), 7.40 (m, 1H), 7.79(d, J = 9.5 Hz, 1H), 7.94-8.06 (m, 2H), 8.71 (s, 1H), 8.73 (s, 1H), 9.32(broad s, 1H), 9.89 (broad s, 1H), 14.27 (broad s, 1H). Mass spectrum(LC-MS-ES+/−): m/z 339 [M + H]⁻, m/z 341 [M + H]⁺ 96 ¹H NMR spectrum(DMSO-d6, δ in ppm): 7.20-7.30 (m, 2H) 7.73-7.82 (m, 2H) 8.00 (dd, J =9.5, 1.7 Hz 1H) 8.71 (s, 2H) 9.32 (broad s, 1H) 10.08 (broad s, 1H)14.25 (broad s, 1H) Mass spectrum (LC-MS-ES+/−): m/z 339 [M + H]⁻, m/z341 [M + H]⁺ 97 ¹H NMR spectrum (DMSO-d6, δ in ppm): 6.93 (tt, J = 9.4,2.2 Hz, 1H), 7.68-7.82 (m, 3H), 7.88 (dd, J = 9.5, 1.7 Hz, 1H), 8.43(broad m, 1H), 8.62 (s, 1H), 9.21 (broad s, 1H), 10.76 (broad s, 1H),15.31 (broad m, 1H). Mass spectrum (LC-MS-ES+/−): m/z 339 [M + H]⁻, m/z341 [M + H]⁺ 98 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.15-7.41 (m, 3H),7.81 (d, J = 9.5 Hz, 1H), 7.89 (dd, J = 9.5, 1.7 Hz, 1H), 8.10 (m, 1H),8.43 (broad m, 1H), 8.61 (s, 1H), 9.20 (broad s, 1H), 9.82 (broad s,1H), 15.31 (broad m, 1H). Mass spectrum (LC-MS-ES+/−): m/z 321 [M + H]⁻,m/z 323 [M + H]⁺ 99 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.05 (m, 1H),7.40 (m, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.82 (dd, J = 9.5, 1.7 Hz, 1H),8.01 (m, 1H), 8.43 (broad m, 1H), 8.64 (s, 1H), 9.20 (broad s, 1H), 9.88(broad s, 1H), 15.31 (broad m, 1H). Mass spectrum (LC-MS-ES+/−): m/z 339[M + H]⁻, m/z 341 [M + H]⁺ 100 ¹H NMR spectrum (DMSO-d6, δ in ppm): 7.20(m, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.77-7.97 (m, 2H), 8.31-8.51 (m,2H), 8.66 (s, 1H), 9.21 (s, 1H), 9.95 (s, 1H), 15.33 (broad m, 1H),(broad signals) Mass spectrum (LC-MS-ES+/−): m/z 337 [M + H]⁻, m/z 339[M + H]⁺

The compounds according to the invention underwent pharmacological teststo determine their modulatory effect on NOT.

Evaluation of the In Vitro Activity on N2A Cells

The activity of the compounds according to the invention was evaluatedon a cell line (N2A) endogenously expressing the murine Nurr 1 receptorand stably transfected with the NOT binding response element (NBRE)coupled to the luciferase reporter gene. The EC₅₀ values are between0.01 and 1000 nM. The tests were performed according to the proceduredescribed hereinbelow.

The cell line Neuro-2A is obtained from a standard commercial source(ATCC). The clone Neuro-2A was obtained from a spontaneous tumouroriginating from a strain of albino mice A by R. J Klebe et al. Thisline Neuro-2A is then stably transfected with 8NBRE-luciferase. TheN2A-8NBRE cells are cultured to the point of confluence in 75 cm²culture flasks containing DMEM supplemented with 10% foetal calf serum,4.5 g/L of glucose and 0.4 mg/ml of geneticin. After culturing for oneweek, the cells are recovered with 0.25% trypsin for 30 seconds and thenresuspended in DMEM without phenol red, containing 4.5 g/L of glucoseand 10% Hyclone defatted serum, and placed in white, transparent-based96-well plates. The cells are deposited at a rate of 60 000 per well in75 μL for 24 hours before adding the products. The products are appliedin 25 μL and incubated for a further 24 hours. On the day ofmeasurement, an equivalent volume (100 μL) of Steadylite is added toeach well, and the wells are then left for 30 minutes to obtain completelysis of the cells and maximum production of the signal. The plates arethen measured in a microplate luminescence counter, after having beensealed with an adhesive film. The products are prepared in the form of a10⁻² M stock solution, and then diluted in 100% of DMSO. Eachconcentration of product is prediluted in culture medium beforeincubation with the cells thus containing 0.625% final of DMSO.

For example, compounds 3, 17, 24, 29, 45 and 53 gave an EC₅₀ value of0.9 nM, 26.8 nM, 0.9 nM, 1.1 nM, 1.2 nM and 0.4 nM, respectively.

It is thus seen that the compounds according to the invention have amodulatory effect on NOT.

The compounds according to the invention may thus be used for thepreparation of medicaments for their therapeutic application in thetreatment or prevention of diseases involving the NOT receptors.

Thus, according to another of its aspects, a subject of the invention ismedicaments comprising a compound of formula (I), or an addition saltthereof with a pharmaceutically acceptable acid.

These medicaments find their therapeutic use especially in the treatmentand prevention of neurodegenerative diseases, for instance Parkinson'sdisease, Alzheimer's disease, tauopathies (e.g. progressive supranuclearpalsy, frontotemporal dementia, corticobasal degeneration, Pick'sdisease); cerebral trauma, for instance ischaemia and cranial trauma andepilepsy; psychiatric diseases, for instance schizophrenia, depression,substance dependency, and attention-deficit hyperactivity disorder;inflammatory diseases of the central nervous system, for instancemultiple sclerosis, encephalitis, myelitis and encephalomyelitis andother inflammatory diseases, for instance vascular pathologies,atherosclerosis, joint inflammations, arthrosis, rheumatoid arthritis;osteoarthritis, Crohn's disease, ulcerative colitis; allergicinflammatory diseases such as asthma, autoimmune diseases, for instancetype 1 diabetes, lupus, scleroderma, Guillain-Barré syndrome, Addison'sdisease and other immune-mediated diseases; osteoporosis; cancers.

Thus, one subject of the present invention is directed towards acompound of formula (I) as defined previously, for the treatment of theabovementioned diseases, complaints and disorders.

According to another of its aspects, the present invention relates tothe use of a compound of formula (I) as defined previously, for thepreparation of a medicament for treating or preventing one of thediseases, complaints or disorders mentioned above.

These compounds may also be used as a treatment combined with graftsand/or transplantations of stem cells.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention. These pharmaceutical compositions contain aneffective dose of at least one compound according to the invention, or apharmaceutically acceptable salt of the said compound, and also at leastone pharmaceutically acceptable excipient.

The said excipients are chosen, according to the pharmaceutical form andthe desired mode of administration, from the usual excipients known tothose skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or the salt thereof, may beadministered in unit administration form, as a mixture with standardpharmaceutical excipients, to man and animals for the prophylaxis ortreatment of the above complaints or diseases.

The appropriate unit forms of administration include oral forms such astablets, soft or hard gel capsules, powders, granules and oral solutionsor suspensions, sublingual, buccal, intratracheal, intraocular,intranasal or inhalation administration forms, topical, transdermal,subcutaneous, intramuscular or intravenous administration forms, rectaladministration forms and implants. For topical application, thecompounds according to the invention may be used in creams, gels,ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mgCroscarmellose sodium 6.0 mg Corn starch 15.0 mgHydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

There may be particular cases in which higher or lower dosages areappropriate; such dosages are not outside the context of the invention.According to the usual practice, the dosage that is appropriate for eachpatient is determined by the doctor according to the mode ofadministration and the weight and response of the said patient.

According to another of its aspects, the present invention also relatesto a method for treating the pathologies indicated above, whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or a pharmaceutically acceptablesalt thereof.

It is understood that all the subjects of the invention defined above,especially the medicaments, pharmaceutical compositions and treatmentmethods, also apply more particularly to the subgroups of compoundspreviously defined.

1-19. (canceled)
 20. A compound selected from the group consisting of:6-Bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide;6-Iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide;N-Phenyl-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide;6-Trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide;N-Phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamideand the hydrobromide (1:1) thereof;2-Phenylcarbamoylimidazo[1,2-a]pyridine-6-boronic acid hydrochloride(1:1); N-Phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide;6-Formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide;6-(2-Bromoacetyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide;6-(1-Ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide;N-(3,5-Difluorophenyl)-6-iodoimidazo[1,2-a]pyridine-2-carboxamide;6-(6-{[(1,1-Dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylicacid; Ethyl 6-(6-aminopyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate;Ethyl6-(6-{[(1,1-dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate;Ethyl6-(6-{bis[(1,1-dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(Pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; Ethyl(6-pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(1-Triphenylmethyl-1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylicacid; Ethyl6-(1-triphenylmethyl-1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(2-{[(1,1-Dimethylethoxy)carbonyl]amino}thiazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylicacid; Ethyl6-(2-{[(1,1-dimethylethoxy)carbonyl]amino}thiazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(1H-Pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid and thehydrochloride (1:1) thereof; Ethyl6-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]imidazo[1,2-a]pyridine-2-carboxylate;6-(1H-Pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; Ethyl6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(1H-Pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; Ethyl6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(Furan-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; Ethyl6-(furan-2-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(Furan-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; Ethyl6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-[5-(Hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxylic acid;Ethyl 6-(5-formylfuran-2-yl)imidazo[1,2-a]pyridine-2-carboxylate; Ethyl6-[5-(hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxylate;6-(Thiophen-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; Ethyl6-(thiophen-3-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(Oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; Ethyl6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(1H-1,2,4-Triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; Ethyl6-[ethoxy(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate; Ethyl6-[hydrazino(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate; Ethyl6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(1H-1,2,3-Triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; Ethyl6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate;6-(1H-1,2,3-Triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; Ethyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxylatehydrobromide (1:1); and 2-Ethoxycarbonylimidazo[1,2-a]pyridine-6-boronicacid.